rs750639846
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2
The NM_144670.6(A2ML1):c.462+16_462+18del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000681 in 1,614,080 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00048 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00070 ( 8 hom. )
Consequence
A2ML1
NM_144670.6 intron
NM_144670.6 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.616
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 -12 ACMG points.
BP6
?
Variant 12-8829787-GGGA-G is Benign according to our data. Variant chr12-8829787-GGGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 445738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High AC in GnomAd4 at 73 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
A2ML1 | NM_144670.6 | c.462+16_462+18del | intron_variant | ENST00000299698.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
A2ML1 | ENST00000299698.12 | c.462+16_462+18del | intron_variant | 1 | NM_144670.6 | P1 | |||
A2ML1-AS1 | ENST00000537288.1 | n.286+872_286+874del | intron_variant, non_coding_transcript_variant | 3 | |||||
A2ML1 | ENST00000537546.1 | n.286+16_286+18del | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.000493 AC: 75AN: 152150Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00135 AC: 337AN: 249488Hom.: 3 AF XY: 0.00177 AC XY: 240AN XY: 135348
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GnomAD4 exome AF: 0.000702 AC: 1026AN: 1461812Hom.: 8 AF XY: 0.000980 AC XY: 713AN XY: 727192
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GnomAD4 genome ? AF: 0.000479 AC: 73AN: 152268Hom.: 0 Cov.: 31 AF XY: 0.000618 AC XY: 46AN XY: 74456
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 18, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | A2ML1: BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 11, 2019 | Variant summary: A2ML1 c.462+16_462+18delGAG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 249488 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is more than 300 higher than the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.462+16_462+18delGAG in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at