rs137853822
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_024312.5(GNPTAB):c.1363G>T(p.Ala455Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,024 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A455V) has been classified as Pathogenic.
Frequency
Consequence
NM_024312.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.1363G>T | p.Ala455Ser | missense_variant | 11/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.1282G>T | p.Ala428Ser | missense_variant | 11/21 | ||
GNPTAB | XM_006719593.4 | c.1363G>T | p.Ala455Ser | missense_variant | 11/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.1363G>T | p.Ala455Ser | missense_variant | 11/21 | 1 | NM_024312.5 | P1 | |
GNPTAB | ENST00000549940.5 | c.1363G>T | p.Ala455Ser | missense_variant | 11/11 | 1 | |||
GNPTAB | ENST00000552009.1 | n.22G>T | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251452Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 727208
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2022 | Variant summary: GNPTAB c.1363G>T (p.Ala455Ser) results in a conservative amino acid change located in the Notch domain (IPR000800) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251452 control chromosomes (gnomAD). c.1363G>T has been reported in the literature in at least one individual affected with stuttering (example: Kang_2010). A different variant affecting the same residue has been observed in two compound heterozygous individuals in one family (c.1364C>T, p.A455V and IVS13+1G>A) affected with Mucolipidosis and the variant segregated with disease (Yu_2019), suggesting that it is a clinically significant residue. In addition, Han_2019 showed this variant produces vocalization deficit in 8-day-old pup isolation calls and does not affect other nonvocal behaviors in mouse model. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 20, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at