rs144876785

Positions:

chr12-8867913-C-G

Variant summary

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

The ENST00000299698.12(A2ML1):c.3789C>G(p.Asn1263Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,614,236 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

A2ML1
ENST00000299698.12 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.644

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:

(HGNC:):

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=0.007165879).

BP6

Variant 12-8867913-C-G is Benign according to our data. Variant chr12-8867913-C-G is described in ClinVar as [Benign]. Clinvar id is 413827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8867913-C-G is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 463 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.3789C>G	p.Asn1263Lys	missense_variant	30/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.3789C>G	p.Asn1263Lys	missense_variant	30/36	1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
	ENST00000631830.1 linkuse as main transcript	n.322-9637G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

463

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.00382

GnomAD3 exomes

AF:

0.000781

AC:

195

AN:

249550

Hom.:

AF XY:

0.000539

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000308

AC:

450

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0117

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.00304

AC:

463

AN:

152354

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.000980

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:

0.00378

Alfa

AF:

0.000537

Hom.:

Bravo

AF:

0.00371

ESP6500AA

AF:

0.00947

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000794

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 14, 2020

Variant summary: A2ML1 c.3789C>G (p.Asn1263Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 280962 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3000 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.7

DANN

Benign

0.46

DEOGEN2

Benign

0.0024

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.55

T;T;T

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.82

N;N;N

REVEL

Benign

0.025

Sift

Benign

0.87

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.091

MutPred

0.47

Gain of methylation at N1263 (P = 0.0167);.;.;

MVP

0.014

MPC

0.12

ClinPred

0.0030

GERP RS

0.78

Varity_R

0.038

gMVP

0.15

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.

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