chr12-8863966-GGC-G
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_144670.6(A2ML1):c.3676_3677delGC(p.Ala1226GlnfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0475 in 1,613,182 control chromosomes in the GnomAD database, including 2,054 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144670.6 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.3676_3677delGC | p.Ala1226GlnfsTer34 | frameshift_variant | Exon 29 of 36 | 1 | NM_144670.6 | ENSP00000299698.7 | ||
A2ML1 | ENST00000541459.5 | c.2326_2327delGC | p.Ala776GlnfsTer34 | frameshift_variant | Exon 18 of 25 | 2 | ENSP00000443174.1 | |||
A2ML1 | ENST00000539547.5 | c.2203_2204delGC | p.Ala735GlnfsTer34 | frameshift_variant | Exon 18 of 25 | 2 | ENSP00000438292.1 | |||
ENSG00000282022 | ENST00000631830.1 | n.322-5692_322-5691delGC | intron_variant | Intron 1 of 1 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0359 AC: 5470AN: 152158Hom.: 134 Cov.: 33
GnomAD3 exomes AF: 0.0432 AC: 10760AN: 249188Hom.: 306 AF XY: 0.0459 AC XY: 6211AN XY: 135238
GnomAD4 exome AF: 0.0487 AC: 71145AN: 1460906Hom.: 1920 AF XY: 0.0496 AC XY: 36049AN XY: 726772
GnomAD4 genome AF: 0.0359 AC: 5468AN: 152276Hom.: 134 Cov.: 33 AF XY: 0.0351 AC XY: 2617AN XY: 74454
ClinVar
Submissions by phenotype
not provided Benign:2
This variant is associated with the following publications: (PMID: 24896146) -
- -
Otitis media Uncertain:1
- -
not specified Benign:1
Variant summary: A2ML1 c.3676_3677delGC (p.Ala1226GlnfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, the variant allele was found at a frequency of 0.043 in 249188 control chromosomes, predominantly at a frequency of 0.068 within the South Asian subpopulation in the gnomAD database, including 87 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17000-folds over 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 South Asian origin. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at