rs199469464
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006662.3(SRCAP):c.7330C>T(p.Arg2444Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SRCAP
NM_006662.3 stop_gained
NM_006662.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.82
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]
Genome browser will be placed here
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 6 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-30737370-C-T is Pathogenic according to our data. Variant chr16-30737370-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30737370-C-T is described in Lovd as [Pathogenic]. Variant chr16-30737370-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SRCAP | NM_006662.3 | c.7330C>T | p.Arg2444Ter | stop_gained | 34/34 | ENST00000262518.9 | NP_006653.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SRCAP | ENST00000262518.9 | c.7330C>T | p.Arg2444Ter | stop_gained | 34/34 | 2 | NM_006662.3 | ENSP00000262518 | P1 | |
| SRCAP | ENST00000411466.7 | c.7330C>T | p.Arg2444Ter | stop_gained | 34/34 | 3 | ENSP00000405186 | P1 | ||
| SRCAP | ENST00000706321.1 | c.7330C>T | p.Arg2444Ter | stop_gained | 34/34 | ENSP00000516346 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461458Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727038
GnomAD4 exome
AF:
AC:
1
AN:
1461458
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727038
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Floating-Harbor syndrome Pathogenic:12Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 34 of 34). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Hood, RL. et al. (2012), Zhang, S. et al. (2019)). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 29, 2013 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Sep 28, 2022 | PVS1, PS2, PM2, PP5 - |
| Pathogenic, no assertion criteria provided | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | May 13, 2022 | This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 15, 2019 | The SRCAP c.7330C>T (p.Arg2444Ter) variant is a stop-gained variant that is the most frequently reported recurrent variant associated with Floating-Harbor syndrome (Nowaczyk et al. 2012). It has been identified in a heterozygous state in at least 24 unrelated individuals and was confirmed to have occurred de novo in at least three (Hood et al. 2012; Nikkel et al. 2013). The p.Arg2444Ter variant is not reported in the Genome Aggregation Databasea in a region of good sequencing coverage. This variant is predicted to result in premature truncation of the SRCAP protein, including loss of the three C-terminal AT-hook motifs involved in DNA binding, and is expected to inhibit CREB-mediated transactivation via a dominant-negative mechanism (Monroy et al. 2001). Based on the collective evidence, the p.Arg2444Ter variant is classified as pathogenic for Floating-Harbor syndrome. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 23, 2021 | ACMG classification criteria: PVS1 strong, PS4 moderate, PM1, PM2, PM6 - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Dec 10, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | - | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030908 / PMID: 22265015 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:9
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 787 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: 25590979, 23621943, 27815143, 31874661, 27206688, 24970356, 25433523, 22965468, 22265015, 27515243, 30425916, 31200758, 31630891, 27899421, 31715605, 33776628, 32939031, 33726816) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 09, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2444*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 787 amino acid(s) of the SRCAP protein. This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 23621943, 24970356, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30908). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | SRCAP: PS2:Very Strong, PVS1:Strong, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
SRCAP-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 17, 2024 | The SRCAP c.7330C>T variant is predicted to result in premature protein termination (p.Arg2444*). This variant was reported to be one of two recurrent pathogenic variants for Floating-Harbor Syndrome (Nikkel et al. 2013. PubMed ID: 23621943; Goff et al. 2013. PubMed ID: 22965468). We have also observed this variant previously at PreventionGenetics in several other affected individuals. This variant is interpreted as pathogenic. - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2022 | The c.7330C>T (p.R2444*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7330. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2444. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 24% of the protein. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.7330C>T, p.R2444* alteration has been previously reported in multiple unrelated patients with Floating-Harbor syndrome (Hood, 2012; Guo, 2014; Seifert, 2014; Zhu, 2015). Based on the available evidence, this alteration is classified as pathogenic. - |
Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Mar 22, 2024 | A heterozygous nonsense variant in exon 34 of the SRCAP gene that results in a stop codon and premature truncation of the protein at codon 2444 (p.Arg2444Ter) was detected. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Apr 26, 2021 | PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate;PP3_supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at