16-30737343-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006662.3(SRCAP):c.7303C>T(p.Arg2435Ter) 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:20 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 27 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/exons	MANE	UniProt
SRCAP	NM_006662.3	c.7303C>T	p.Arg2435Ter	stop_gained	34/34	ENST00000262518.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRCAP	ENST00000262518.9	c.7303C>T	p.Arg2435Ter	stop_gained	34/34	2	NM_006662.3	P1
SRCAP	ENST00000411466.7	c.7303C>T	p.Arg2435Ter	stop_gained	34/34	3		P1
SRCAP	ENST00000706321.1	c.7303C>T	p.Arg2435Ter	stop_gained	34/34			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Floating-Harbor syndrome Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	May 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 24, 2023	PVS1, PM2, PP5 -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2023

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
MutationTaster	Benign	1.0	A;A;A
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;