rs863224954

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144670.6(A2ML1):​c.2428G>A​(p.Ala810Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

3
9
7

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.73
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
A2ML1NM_144670.6 linkuse as main transcriptc.2428G>A p.Ala810Thr missense_variant 19/36 ENST00000299698.12 NP_653271.3 B3KVV6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
A2ML1ENST00000299698.12 linkuse as main transcriptc.2428G>A p.Ala810Thr missense_variant 19/361 NM_144670.6 ENSP00000299698.7 A8K2U0-1
A2ML1ENST00000541459.5 linkuse as main transcriptc.1078G>A p.Ala360Thr missense_variant 8/252 ENSP00000443174.1 H0YGG5
A2ML1ENST00000539547.5 linkuse as main transcriptc.955G>A p.Ala319Thr missense_variant 8/252 ENSP00000438292.1 A8K2U0-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Nonsyndromic otitis media Uncertain:1
Uncertain significance, no assertion criteria providedresearchDepartment of Molecular and Human Genetics, Baylor College of MedicineMay 28, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.028
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.016
T;T;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.90
D;D;D
MetaSVM
Benign
-0.85
T
MutationAssessor
Pathogenic
3.5
H;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.6
D;D;D
REVEL
Uncertain
0.33
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.87
MutPred
0.81
Loss of methylation at R807 (P = 0.0708);.;.;
MVP
0.36
MPC
0.52
ClinPred
1.0
D
GERP RS
2.7
Varity_R
0.69
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224954; hg19: chr12-9004573; API