rs138301233

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_144670.6(A2ML1):c.2027G>A(p.Arg676Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,610,310 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R676W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

A2ML1
NM_144670.6 missense, splice_region

Scores

Splicing: ADA: 0.00004369

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055425763).

BP6

Variant 12-8848913-G-A is Benign according to our data. Variant chr12-8848913-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8848913-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.2027G>A	p.Arg676Gln	missense_variant, splice_region_variant	16/36	ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.2027G>A	p.Arg676Gln	missense_variant, splice_region_variant	16/36	1	NM_144670.6	P1	A8K2U0-1
A2ML1	ENST00000541459.5 linkuse as main transcript	c.677G>A	p.Arg226Gln	missense_variant, splice_region_variant	5/25	2
A2ML1	ENST00000539547.5 linkuse as main transcript	c.554G>A	p.Arg185Gln	missense_variant, splice_region_variant	5/25	2			A8K2U0-2
A2ML1	ENST00000545692.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000208

AC:

AN:

244686

Hom.:

AF XY:

0.0000979

AC XY:

AN XY:

132730

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000844

AC:

123

AN:

1458058

Hom.:

Cov.:

AF XY:

0.0000731

AC XY:

AN XY:

725204

show subpopulations

Gnomad4 AFR exome

AF:

0.00253

Gnomad4 AMR exome

AF:

0.000295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152252

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000805

ESP6500AA

AF:

0.00288

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000215

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2022	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

Cadd

Benign

Dann

Benign

0.44

DEOGEN2

Benign

0.0045

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.0055

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.97

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.95

T;T;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.064

MVP

0.072

MPC

0.12

ClinPred

0.0092

GERP RS

0.59

Varity_R

0.030

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over