rs200462659
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_144670.6(A2ML1):āc.2749T>Cā(p.Leu917=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00041 ( 0 hom., cov: 32)
Exomes š: 0.00060 ( 0 hom. )
Consequence
A2ML1
NM_144670.6 synonymous
NM_144670.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.22
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 -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
?
Variant 12-8854816-T-C is Benign according to our data. Variant chr12-8854816-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 413808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8854816-T-C is described in Lovd as [Likely_benign]. Variant chr12-8854816-T-C is described in Lovd as [Benign].
BS2
?
High AC in GnomAd4 at 63 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.2749T>C | p.Leu917= | synonymous_variant | 22/36 | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.2749T>C | p.Leu917= | synonymous_variant | 22/36 | 1 | NM_144670.6 | P1 | |
A2ML1 | ENST00000541459.5 | c.1399T>C | p.Leu467= | synonymous_variant | 11/25 | 2 | |||
A2ML1 | ENST00000539547.5 | c.1276T>C | p.Leu426= | synonymous_variant | 11/25 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000414 AC: 63AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000461 AC: 115AN: 249422Hom.: 0 AF XY: 0.000384 AC XY: 52AN XY: 135348
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GnomAD4 exome AF: 0.000601 AC: 878AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.000597 AC XY: 434AN XY: 727184
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GnomAD4 genome ? AF: 0.000414 AC: 63AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27AN XY: 74462
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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:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 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 | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 04, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at