NM_006662.3:c.7303C>T

Variant names:

• chr16-30737343-C-T
• rs199469465
• NM_006662.3:c.7303C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006662.3(SRCAP):​c.7303C>T​(p.Arg2435*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRCAP NM_006662.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: -0.167

Genes affected

SRCAP (HGNC:16974): (Snf2 related CREBBP activator protein) This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome, a rare disorder characterized by short stature, language deficits and dysmorphic facial features. [provided by RefSeq, Feb 2012]

ENSG00000282034 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30737343-C-T is Pathogenic according to our data. Variant chr16-30737343-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30737343-C-T is described in Lovd as [Pathogenic]. Variant chr16-30737343-C-T is described in Lovd as [Pathogenic]. Variant chr16-30737343-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRCAP	NM_006662.3	c.7303C>T	p.Arg2435*	stop_gained	Exon 34 of 34	ENST00000262518.9	NP_006653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRCAP	ENST00000262518.9	c.7303C>T	p.Arg2435*	stop_gained	Exon 34 of 34	2	NM_006662.3	ENSP00000262518.4
ENSG00000282034	ENST00000380361.7	n.6772C>T		non_coding_transcript_exon_variant	Exon 29 of 31	2		ENSP00000369719.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Floating-Harbor syndrome Pathogenic:13 Other:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is the likely mechanism of disease in this gene relating to the cluster of pathogenic protein truncating variants in SRCAP exons 33 and 34 and associated Floating-Harbor syndrome (MIM#136140) (PMID: 22265015, GeneReviews) while the disease mechanism associated with missense variants is currently unclear. It should also be noted that haploinsufficiency has been suggested for pathogenic variants associated with the newly described ‘non-Floating-Harbor syndrome SRCAP-related neurodevelopmental disorder’ (PMID: 33909990). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants associated with Floating-Harbor syndrome (GeneReviews). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been described as a recurrent pathogenic variant in individuals with Floating-Harbor syndrome (ClinVar, PMIDs: 31200758, 33909990). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PM6_VeryStrong+PP4 -

Apr 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SRCAP c.7303C>T (p.Arg2435X) results in a premature termination codon which is not expected to undergo nonsense mediated decay, however does disrupt the last 796 amino acids of the protein. The variant was absent in 249920 control chromosomes. c.7303C>T has been reported in the literature in individuals affected with Floating-Harbor Syndrome, including cases where de novo inheritance was confirmed (Hood_2012, Lee_2014, Tonne_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22265015, 25326637, 33288889). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 15, 2016

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SRCAP c.7303C>T (p.Arg2435Ter) nonsense variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay, although multiple downstream truncating variants are considered causative in the literature (PMID: 35664296). This variant has been identified in multiple individuals with a phenotype consistent with Floating-Harbor syndrome and was confirmed as de novo in several individuals (PMID: 23621943; 22265015; 34006472). The c.7303C>T variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by multiple submitters in ClinVar. The c.7303C>T variant was identified in a de novo state. Based on the available evidence, the c.7303C>T (p.Arg2435Ter) variant is classified as pathogenic for Floating-Harbor syndrome. -

Feb 24, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP5 -

May 20, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2024

Children's Health, Guangyuan Central Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The c.7303C>T (p.R2435X) alteration, located in exon 34 of the SRCAP gene, consists of a C to T substitution at nucleotide position 7303. This changes the amino acid at position 2435 from arginine (R) to a stop codon. It is expected to cause truncation of encoded proteins or loss of proteins due to nonsense mediated decay, which is a well-known disease mechanism. This mutation has not been reported in population-based cohorts in the Genome Aggregation Database (gnomAD). c. The change of 7303C>T has been found in multiple patients with floating port syndrome (Jeon, Noh,&Hwang, 2024; Seifert et al., 2014; Zhang et al., 2019). The three ClinVar submissions all listed this variant as pathogenic. The variant is classified as pathogenic, according to ACMG Guidelines (2015). These data indicate that this mutation is likely related to disease. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:9

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg2435*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 796 amino acid(s) of the SRCAP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 22965468, 23621943, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30909). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 796 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23165645, 22265015, 25433523, 26788936, 22965468, 20358590, 31200758, 31248274, 31607746, 31605816, 32170002, 34006472) -

Dec 18, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7303C>T (p.R2435*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7303. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2435. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 24.6% of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data)._x000D_ _x000D_ This variant is expected to be causative of Floating-Harbor syndrome; however, its clinical significance for SRCAP-related neurodevelopmental disorder is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple individuals with features consistent with Floating-Harbor syndrome, including multiple cases of reported de novo occurrence (Hood, 2012; Reschen, 2012; Le Goff, 2013; Nikkel, 2013; Seifert, 2014; Yagi, 2016; Homma, 2019; Zhang, 2019; Lee, 2020; Squeo, 2020). This alteration demonstrated a DNA methylation episignature consistent with Floating-Harbor Syndrome on a genome-wide DNA methylation assay (Kerkhof, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.28	N
Vest4		0.89
GERP RS		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199469465; hg19: chr16-30748664;