rs199469466
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_006662.3(SRCAP):c.7549del(p.Gln2517LysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SRCAP
NM_006662.3 frameshift
NM_006662.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.00600
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 Likely_pathogenic. Variant got 8 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. Fraction of 0.221 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-30737586-GC-G is Pathogenic according to our data. Variant chr16-30737586-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 30910.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-30737586-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SRCAP | NM_006662.3 | c.7549del | p.Gln2517LysfsTer5 | frameshift_variant | 34/34 | ENST00000262518.9 | NP_006653.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SRCAP | ENST00000262518.9 | c.7549del | p.Gln2517LysfsTer5 | frameshift_variant | 34/34 | 2 | NM_006662.3 | ENSP00000262518 | P1 | |
SRCAP | ENST00000411466.7 | c.7549del | p.Gln2517LysfsTer5 | frameshift_variant | 34/34 | 3 | ENSP00000405186 | P1 | ||
SRCAP | ENST00000706321.1 | c.7549del | p.Gln2517LysfsTer5 | frameshift_variant | 34/34 | ENSP00000516346 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2023 | The c.7549delC (p.Q2517Kfs*5) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a deletion of one nucleotide at position 7549, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 22% of the protein. Premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data)._x000D_ _x000D_ for Floating-Harbor syndrome; however, its clinical significance for SRCAP-related neurodevelopmental disorder is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual with features consistent with Floating-Harbor syndrome (Hood, 2012). Based on the available evidence, this alteration is classified as pathogenic. - |
Floating-Harbor syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 10, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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