NM_006662.3:c.7303C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_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

Scores

2
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: -0.167
Variant links:
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]

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ACMG classification

Classification made for transcript

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
SRCAPNM_006662.3 linkc.7303C>T p.Arg2435* stop_gained Exon 34 of 34 ENST00000262518.9 NP_006653.2 Q6ZRS2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRCAPENST00000262518.9 linkc.7303C>T p.Arg2435* stop_gained Exon 34 of 34 2 NM_006662.3 ENSP00000262518.4 Q6ZRS2-1
ENSG00000282034ENST00000380361.7 linkn.6772C>T non_coding_transcript_exon_variant Exon 29 of 31 2 ENSP00000369719.3 A0A0C4DFX4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Floating-Harbor syndrome Pathogenic:13Other:1
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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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 -

May 20, 2014
UCLA Clinical Genomics Center, UCLA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Aug 15, 2016
Undiagnosed Diseases Network, NIH
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
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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. -

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 -

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

- -

-
Department of Medical Genetics, Oslo University Hospital
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 -

not provided Pathogenic:9
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
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

- -

Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199469465; hg19: chr16-30748664; API