rs56179521

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_144670.6(A2ML1):c.2868C>T(p.Ala956Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,612,308 control chromosomes in the GnomAD database, including 2,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 174 hom., cov: 30)

Exomes 𝑓: 0.048 ( 2100 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.631

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen, Orphanet

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 12-8857183-C-T is Benign according to our data. Variant chr12-8857183-C-T is described in ClinVar as Benign. ClinVar VariationId is 384725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.631 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.2868C>T	p.Ala956Ala	synonymous_variant	Exon 24 of 36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
A2ML1	ENST00000299698.12 link	c.2868C>T	p.Ala956Ala	synonymous_variant	Exon 24 of 36	1	NM_144670.6	ENSP00000299698.7
A2ML1	ENST00000541459.5 link	c.1518C>T	p.Ala506Ala	synonymous_variant	Exon 13 of 25	2		ENSP00000443174.1
A2ML1	ENST00000539547.5 link	c.1395C>T	p.Ala465Ala	synonymous_variant	Exon 13 of 25	2		ENSP00000438292.1
A2ML1	ENST00000545850.1 link	n.-52C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5638

AN:

152044

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00930

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0536

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0379

AC:

9448

AN:

249278

AF XY:

0.0388

show subpopulations

Gnomad AFR exome

AF:

0.00756

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0484

AC:

70658

AN:

1460146

Hom.:

2100

Cov.:

AF XY:

0.0475

AC XY:

34500

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.00568

AC:

190

AN:

33428

American (AMR)

AF:

0.0145

AC:

649

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

349

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0149

AC:

1280

AN:

86172

European-Finnish (FIN)

AF:

0.105

AC:

5623

AN:

53414

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

4406

European-Non Finnish (NFE)

AF:

0.0542

AC:

60218

AN:

1111944

Other (OTH)

AF:

0.0382

AC:

2303

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3558

7116

10675

14233

17791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2228

4456

6684

8912

11140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0370

AC:

5637

AN:

152162

Hom.:

174

Cov.:

AF XY:

0.0382

AC XY:

2844

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00927

AC:

385

AN:

41514

American (AMR)

AF:

0.0165

AC:

252

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0137

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.110

AC:

1167

AN:

10574

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0536

AC:

3647

AN:

68014

Other (OTH)

AF:

0.0246

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

267

535

802

1070

1337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0447

Hom.:

111

Bravo

AF:

0.0295

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0475

EpiControl

AF:

0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The A2ML1 c.2868C>T (p.Ala956Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4589/120498 control chromosomes (135 homozygotes) at a frequency of 0.0380836, which is approximately 9521 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. It has also been reported as a non-pathogenic variant in literature (Vissers_2015). Taken together, this variant is classified as benign.

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Otitis media, susceptibility to

Benign:1

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

6.3

(source)

DANN

Benign

0.60

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over