12-8843160-A-T
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7
The NM_144670.6(A2ML1):c.1275A>T(p.Val425Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 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 (★). Synonymous variant affecting the same amino acid position (i.e. V425V) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
A2ML1
NM_144670.6 synonymous
NM_144670.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.208
Publications
8 publications found
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]
A2ML1 Gene-Disease associations (from GenCC):
- Noonan syndromeInheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 12-8843160-A-T is Benign according to our data. Variant chr12-8843160-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1766335.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.208 with no splicing effect.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_144670.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| A2ML1 | NM_144670.6 | MANE Select | c.1275A>T | p.Val425Val | synonymous | Exon 12 of 36 | NP_653271.3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| A2ML1 | ENST00000299698.12 | TSL:1 MANE Select | c.1275A>T | p.Val425Val | synonymous | Exon 12 of 36 | ENSP00000299698.7 | ||
| A2ML1 | ENST00000541459.5 | TSL:2 | c.-76A>T | upstream_gene | N/A | ENSP00000443174.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000401 AC: 1AN: 249524 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
249524
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727234 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1461852
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727234
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1111986
Other (OTH)
AF:
AC:
0
AN:
60394
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
EpiCase
AF:
EpiControl
AF:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Likely benign
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
-
1
not specified (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.