rs376655036
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_144670.6(A2ML1):c.2231T>C(p.Ile744Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000609 in 1,609,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I744I) has been classified as Likely benign.
Frequency
Consequence
NM_144670.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.2231T>C | p.Ile744Thr | missense_variant | 18/36 | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.2231T>C | p.Ile744Thr | missense_variant | 18/36 | 1 | NM_144670.6 | P1 | |
A2ML1 | ENST00000541459.5 | c.881T>C | p.Ile294Thr | missense_variant | 7/25 | 2 | |||
A2ML1 | ENST00000539547.5 | c.758T>C | p.Ile253Thr | missense_variant | 7/25 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000448 AC: 11AN: 245748Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133474
GnomAD4 exome AF: 0.0000611 AC: 89AN: 1457454Hom.: 0 Cov.: 29 AF XY: 0.0000524 AC XY: 38AN XY: 725138
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74400
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2017 | The I744T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 2/18542 (0.011%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al., 2016). I744T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, yet in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 01, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 406198). This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. This variant is present in population databases (rs376655036, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 744 of the A2ML1 protein (p.Ile744Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at