rs1396379503
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001372044.2(SHANK3):c.2451+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,558,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001372044.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SHANK3 | NM_001372044.2 | c.2451+1G>A | splice_donor_variant, intron_variant | Intron 22 of 24 | NP_001358973.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SHANK3 | ENST00000262795.7 | c.1866+1G>A | splice_donor_variant, intron_variant | Intron 18 of 21 | 5 | ENSP00000489147.3 | ||||
SHANK3 | ENST00000445220.7 | c.918+1G>A | splice_donor_variant, intron_variant | Intron 9 of 12 | 5 | |||||
SHANK3 | ENST00000664402.2 | c.408+1G>A | splice_donor_variant, intron_variant | Intron 3 of 6 | ENSP00000499475.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000142 AC: 2AN: 1406414Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 694700
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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Reported previously as c.2313+1G>A using alternate nomenclature in association with SHANK3-related disorders (Holder et al., 2016); Published functional studies demonstrate abnormal splicing and support instability of the resulting mRNA (Li et al., 2018); Canonical splice site variant in the 5' region of the gene where loss-of-function has not been definitively established as a disease mechanism (PMID 28179641); This variant is associated with the following publications: (PMID: 28263302, 25724810, 29719671, 29023665, 30537371, 27554343) -
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Phelan-McDermid syndrome Pathogenic:4
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ACMG Criteria: PVS1, PS3, PM2_P, PP3, PP5; Variant was found in heterozygous state -
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Neurodevelopmental abnormality Pathogenic:1
PVS1, PS4 -
Inborn genetic diseases Pathogenic:1
The c.2265+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 19 of the SHANK3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/163960) total alleles studied. The SHANK3 c.2265+1G>A alteration was flagged as a low confidence call 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 Phelan-McDermid syndrome (Li, 2018). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at