rs61745125
Positions:
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_144670.6(A2ML1):c.3252C>T(p.His1084=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,614,110 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0047 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0054 ( 44 hom. )
Consequence
A2ML1
NM_144670.6 synonymous
NM_144670.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.802
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 -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
?
Variant 12-8858090-C-T is Benign according to our data. Variant chr12-8858090-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8858090-C-T is described in Lovd as [Likely_benign]. Variant chr12-8858090-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.802 with no splicing effect.
BS2
?
High AC in GnomAd4 at 716 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.3252C>T | p.His1084= | synonymous_variant | 26/36 | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.3252C>T | p.His1084= | synonymous_variant | 26/36 | 1 | NM_144670.6 | P1 | |
A2ML1 | ENST00000541459.5 | c.1902C>T | p.His634= | synonymous_variant | 15/25 | 2 | |||
A2ML1 | ENST00000539547.5 | c.1779C>T | p.His593= | synonymous_variant | 15/25 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00470 AC: 716AN: 152182Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00495 AC: 1233AN: 249320Hom.: 5 AF XY: 0.00479 AC XY: 648AN XY: 135276
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GnomAD4 exome AF: 0.00536 AC: 7839AN: 1461810Hom.: 44 Cov.: 32 AF XY: 0.00524 AC XY: 3811AN XY: 727196
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GnomAD4 genome ? AF: 0.00470 AC: 716AN: 152300Hom.: 3 Cov.: 32 AF XY: 0.00520 AC XY: 387AN XY: 74472
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | A2ML1: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2016 | 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 specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
A2ML1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 16, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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