rs79067860
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_144670.6(A2ML1):c.2295G>A(p.Ala765=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,166 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0088 ( 20 hom., cov: 32)
Exomes 𝑓: 0.00083 ( 14 hom. )
Consequence
A2ML1
NM_144670.6 synonymous
NM_144670.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.76
Genes affected
A2ML1 (HGNC:23336): (alpha-2-macroglobulin like 1) This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 12-8851844-G-A is Benign according to our data. Variant chr12-8851844-G-A is described in ClinVar as [Benign]. Clinvar id is 241891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8851844-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-2.76 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00884 (1346/152278) while in subpopulation AFR AF= 0.0299 (1244/41546). AF 95% confidence interval is 0.0286. There are 20 homozygotes in gnomad4. There are 634 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1346 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.2295G>A | p.Ala765= | synonymous_variant | 19/36 | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.2295G>A | p.Ala765= | synonymous_variant | 19/36 | 1 | NM_144670.6 | P1 | |
A2ML1 | ENST00000541459.5 | c.945G>A | p.Ala315= | synonymous_variant | 8/25 | 2 | |||
A2ML1 | ENST00000539547.5 | c.822G>A | p.Ala274= | synonymous_variant | 8/25 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00878 AC: 1336AN: 152160Hom.: 20 Cov.: 32
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GnomAD3 exomes AF: 0.00220 AC: 548AN: 249554Hom.: 4 AF XY: 0.00173 AC XY: 234AN XY: 135396
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GnomAD4 exome AF: 0.000833 AC: 1218AN: 1461888Hom.: 14 Cov.: 30 AF XY: 0.000708 AC XY: 515AN XY: 727244
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GnomAD4 genome ? AF: 0.00884 AC: 1346AN: 152278Hom.: 20 Cov.: 32 AF XY: 0.00851 AC XY: 634AN XY: 74462
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at