rs200983183
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The ENST00000299698.12(A2ML1):c.1368C>T(p.His456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,614,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 1 hom. )
Consequence
A2ML1
ENST00000299698.12 synonymous
ENST00000299698.12 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.45
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 -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 12-8843253-C-T is Benign according to our data. Variant chr12-8843253-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8843253-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.45 with no splicing effect.
BS2
High AC in GnomAd4 at 28 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.1368C>T | p.His456= | synonymous_variant | 12/36 | ENST00000299698.12 | NP_653271.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.1368C>T | p.His456= | synonymous_variant | 12/36 | 1 | NM_144670.6 | ENSP00000299698 | P1 | |
A2ML1 | ENST00000541459.5 | c.18C>T | p.His6= | synonymous_variant | 1/25 | 2 | ENSP00000443174 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000248 AC: 62AN: 249584Hom.: 0 AF XY: 0.000251 AC XY: 34AN XY: 135408
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GnomAD4 exome AF: 0.000235 AC: 344AN: 1461890Hom.: 1 Cov.: 32 AF XY: 0.000216 AC XY: 157AN XY: 727244
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GnomAD4 genome AF: 0.000184 AC: 28AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74506
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 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, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2020 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
A2ML1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 09, 2020 | This variant is classified as likely 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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at