rs61744220

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144670.6(A2ML1):c.1109T>C(p.Phe370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,056 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 177 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 177 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.0210

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014653802).

BP6

Variant 12-8841397-T-C is Benign according to our data. Variant chr12-8841397-T-C is described in ClinVar as [Benign]. Clinvar id is 120251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.1109T>C	p.Phe370Ser	missense_variant	Exon 11 of 36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 link	c.1109T>C	p.Phe370Ser	missense_variant	Exon 11 of 36	1	NM_144670.6	ENSP00000299698.7		A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.0263

AC:

4003

AN:

152116

Hom.:

176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0911

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00670

AC:

1671

AN:

249494

AF XY:

0.00464

show subpopulations

Gnomad AFR exome

AF:

0.0927

Gnomad AMR exome

AF:

0.00481

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00271

AC:

3965

AN:

1461822

Hom.:

177

Cov.:

AF XY:

0.00226

AC XY:

1644

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0933

AC:

3119

AN:

33438

American (AMR)

AF:

0.00577

AC:

258

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000220

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000165

AC:

184

AN:

1112004

Other (OTH)

AF:

0.00575

AC:

347

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

167

335

502

670

837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0263

AC:

4007

AN:

152234

Hom.:

177

Cov.:

AF XY:

0.0254

AC XY:

1892

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0909

AC:

3776

AN:

41522

American (AMR)

AF:

0.0115

AC:

175

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68030

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

184

368

551

735

919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00893

Hom.:

121

Bravo

AF:

0.0298

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0808

AC:

308

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00803

AC:

970

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 06, 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.1109T>C (p.Phe370Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 967/120708 control chromosomes (48 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.089778 (880/9802). This frequency is about 22444 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a benign common polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory (via ClinVar) has classified this variant as benign. Taken together, this variant is classified as benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 22, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0043

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.021

PrimateAI

Benign

0.39

PROVEAN

Benign

1.2

REVEL

Benign

0.032

Sift

Benign

0.51

Sift4G

Benign

0.56

Polyphen

0.0010

Vest4

0.19

MVP

0.048

MPC

0.19

ClinPred

0.0014

GERP RS

2.8

Varity_R

0.077

gMVP

0.59

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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rs61744220

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