19-1912477-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_138422.4(ADAT3):c.430G>A(p.Val144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,500,450 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 Likely pathogenic (★★).
Frequency
Consequence
NM_138422.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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ADAT3 | ENST00000329478.4 | c.430G>A | p.Val144Met | missense_variant | Exon 2 of 2 | 1 | NM_138422.4 | ENSP00000332448.2 | ||
SCAMP4 | ENST00000316097.13 | c.-41-2502G>A | intron_variant | Intron 1 of 6 | 1 | NM_079834.4 | ENSP00000316007.7 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000445 AC: 6AN: 1348432Hom.: 0 Cov.: 30 AF XY: 0.00000601 AC XY: 4AN XY: 665022
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
Intellectual disability-strabismus syndrome Pathogenic:15
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's status in the patients using Sanger sequencing and detected it in a heterozygous status in their parents. Multiple reports previously classified the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) as pathogenic (Alazami et al., 2013; El-Hattab et al., 2016). -
The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also have mental retardation was a carrier for this variant. The p.Val144Met variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously reported in patients with intellectual disability and considered as founder mutation in the Saudi Arabian population [PMID: 26842963, 23620220, 32214227]. Functional studies using cell lines derived from intellectual disability-affected individuals showed a severe reduction in tRNA deaminase activity [PMID: 31263000]. -
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not provided Pathogenic:3
In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.V128M; This variant is associated with the following publications: (PMID: 32860008, 31130284, 37644014, 34374989, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220, 38168508) -
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Neurodevelopmental disorder with brain abnormalities Pathogenic:1
PM3,PS3,PM2,PP3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at