rs79149293

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_144670.6(A2ML1):c.158C>G(p.Thr53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,614,110 control chromosomes in the GnomAD database, including 13 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 13 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.26

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:

A2ML1-AS1 (HGNC:41022): (A2ML1 antisense RNA 1)

A2ML1-AS1 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=0.018659174).

BP6

Variant 12-8823277-C-G is Benign according to our data. Variant chr12-8823277-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 413807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8823277-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.158C>G	p.Thr53Arg	missense_variant	Exon 2 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.158C>G	p.Thr53Arg	missense_variant	Exon 2 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1-AS1	ENST00000537288.1 link	n.286+7385G>C		intron_variant	Intron 1 of 1	3
A2ML1	ENST00000537546.1 link	n.-236C>G		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00214

AC:

535

AN:

249546

Hom.:

AF XY:

0.00217

AC XY:

294

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.000835

Gnomad NFE exome

AF:

0.00343

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00361

AC:

5274

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

2599

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.000786

Gnomad4 NFE exome

AF:

0.00431

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152260

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00271

Hom.:

Bravo

AF:

0.00185

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000264

AC:

ESP6500EA

AF:

0.00389

AC:

ExAC

AF:

0.00237

AC:

287

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 26, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: A2ML1 c.158C>G (p.Thr53Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 249546 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 850 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 Non-Finnish European origin. To our knowledge, no occurrence of c.158C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as 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

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0062

Eigen

Benign

0.040

Eigen_PC

Benign

0.0053

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

M_CAP

Benign

0.0089

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.22

Sift

Benign

0.25

Sift4G

Benign

0.49

Polyphen

0.99

Vest4

0.65

MVP

0.076

MPC

0.50

ClinPred

0.023

GERP RS

3.4

Varity_R

0.16

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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