12-8822706-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_144670.6(A2ML1):​c.55G>A​(p.Glu19Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Consequence

A2ML1
NM_144670.6 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.00200
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]
A2ML1-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.035844892).
BP6
Variant 12-8822706-G-A is Benign according to our data. Variant chr12-8822706-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2449320.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
A2ML1NM_144670.6 linkc.55G>A p.Glu19Lys missense_variant Exon 1 of 36 ENST00000299698.12 NP_653271.3 B3KVV6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
A2ML1ENST00000299698.12 linkc.55G>A p.Glu19Lys missense_variant Exon 1 of 36 1 NM_144670.6 ENSP00000299698.7 A8K2U0-1
A2ML1-AS1ENST00000537288.1 linkn.286+7956C>T intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461810
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 19 of the A2ML1 protein (p.Glu19Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with A2ML1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2449320). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1
Nov 02, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
1.9
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0027
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0073
N
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.0018
T
MetaRNN
Benign
0.036
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-1.1
N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.57
N
REVEL
Benign
0.10
Sift
Benign
0.68
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.094
MutPred
0.43
Gain of ubiquitination at E19 (P = 0.0146);
MVP
0.040
MPC
0.12
ClinPred
0.14
T
GERP RS
-0.85
Varity_R
0.040
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1720800547; hg19: chr12-8975302; API