rs200964353
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2
The NM_144670.6(A2ML1):c.3269G>A(p.Gly1090Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00102 in 1,613,980 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1090A) has been classified as Uncertain significance.
Frequency
Consequence
NM_144670.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.3269G>A | p.Gly1090Asp | missense_variant | 27/36 | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.3269G>A | p.Gly1090Asp | missense_variant | 27/36 | 1 | NM_144670.6 | P1 | |
ENST00000631830.1 | n.322-2609C>T | intron_variant, non_coding_transcript_variant | 3 | ||||||
A2ML1 | ENST00000541459.5 | c.1919G>A | p.Gly640Asp | missense_variant | 16/25 | 2 | |||
A2ML1 | ENST00000539547.5 | c.1796G>A | p.Gly599Asp | missense_variant | 16/25 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000730 AC: 111AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000685 AC: 171AN: 249556Hom.: 0 AF XY: 0.000650 AC XY: 88AN XY: 135384
GnomAD4 exome AF: 0.00105 AC: 1530AN: 1461872Hom.: 5 Cov.: 31 AF XY: 0.00101 AC XY: 734AN XY: 727234
GnomAD4 genome ? AF: 0.000730 AC: 111AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46AN XY: 74306
ClinVar
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2019 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2019 | Variant summary: A2ML1 c.3269G>A (p.Gly1090Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 249556 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 325 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at