dbSNP rs143603619: A2ML1:p.Ser1184Arg (chr12-8863841-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144670.6(A2ML1):c.3550A>C(p.Ser1184Arg) 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 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.155

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 links:

ENSG00000282022 (HGNC:):

ENSG00000282022 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070925474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.3550A>C	p.Ser1184Arg	missense_variant	Exon 29 of 36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
A2ML1	ENST00000299698.12 link	c.3550A>C	p.Ser1184Arg	missense_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.2200A>C	p.Ser734Arg	missense_variant	Exon 18 of 25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.2077A>C	p.Ser693Arg	missense_variant	Exon 18 of 25	2		ENSP00000438292.1	A8K2U0-2
ENSG00000282022	ENST00000631830.1 link	n.322-5565T>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.6

DANN

Benign

0.87

DEOGEN2

Benign

0.0072

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.62

T;T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

L;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.041

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.024

B;.;.

Vest4

0.18

MutPred

0.46

Loss of glycosylation at S1184 (P = 0.0249);.;.;

MVP

0.014

MPC

0.13

ClinPred

0.064

GERP RS

-3.3

Varity_R

0.039

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over