chr22-50720865-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001372044.2(SHANK3):c.3218G>T(p.Gly1073Val) variant causes a missense change. The variant allele was found at a frequency of 0.000827 in 1,374,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1073A) has been classified as Likely benign.
Frequency
Consequence
NM_001372044.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHANK3 | NM_001372044.2 | c.3218G>T | p.Gly1073Val | missense_variant | 24/25 | ENST00000710353.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHANK3 | ENST00000262795.7 | c.2633G>T | p.Gly878Val | missense_variant | 20/22 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000601 AC: 90AN: 149810Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00105 AC: 24AN: 22808Hom.: 0 AF XY: 0.00103 AC XY: 14AN XY: 13592
GnomAD4 exome AF: 0.000855 AC: 1047AN: 1224232Hom.: 1 Cov.: 34 AF XY: 0.000843 AC XY: 502AN XY: 595206
GnomAD4 genome ? AF: 0.000600 AC: 90AN: 149918Hom.: 0 Cov.: 33 AF XY: 0.000533 AC XY: 39AN XY: 73188
ClinVar
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2020 | This variant is associated with the following publications: (PMID: 25188300, 20385823, 28371232) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SHANK3: BS1 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2023 | Variant summary: SHANK3 c.3257G>T (p.Arg1086Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 127098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3257G>T in individuals affected with Phelan-McDermid Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
SHANK3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 22, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at