chr12-8863977-A-G

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.3686A>G(p.His1229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,612,776 control chromosomes in the GnomAD database, including 797,653 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1229C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.97 ( 71742 hom., cov: 31)

Exomes 𝑓: 1.0 ( 725911 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.46

Publications

21 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:

ENSG00000282022 (HGNC:):

ENSG00000282022 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=1.4597877E-6).

BP6

Variant 12-8863977-A-G is Benign according to our data. Variant chr12-8863977-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.3686A>G	p.His1229Arg	missense_variant	Exon 29 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.3686A>G	p.His1229Arg	missense_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.2336A>G	p.His779Arg	missense_variant	Exon 18 of 25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.2213A>G	p.His738Arg	missense_variant	Exon 18 of 25	2		ENSP00000438292.1	A8K2U0-2
ENSG00000282022	ENST00000631830.1 link	n.322-5701T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.970

AC:

147533

AN:

152160

Hom.:

71687

Cov.:

show subpopulations

Gnomad AFR

AF:

0.895

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.987

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.978

GnomAD2 exomes

AF:

0.993

AC:

247340

AN:

249146

AF XY:

0.995

show subpopulations

Gnomad AFR exome

AF:

0.896

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.997

AC:

1455922

AN:

1460498

Hom.:

725911

Cov.:

AF XY:

0.997

AC XY:

724670

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.890

AC:

29749

AN:

33442

American (AMR)

AF:

0.994

AC:

44471

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26136

AN:

26136

East Asian (EAS)

AF:

0.999

AC:

39645

AN:

39698

South Asian (SAS)

AF:

1.00

AC:

86143

AN:

86150

European-Finnish (FIN)

AF:

1.00

AC:

53405

AN:

53406

Middle Eastern (MID)

AF:

0.996

AC:

4751

AN:

4768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111758

AN:

1111914

Other (OTH)

AF:

0.993

AC:

59864

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21658

43316

64974

86632

108290

<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:

0.970

AC:

147649

AN:

152278

Hom.:

71742

Cov.:

AF XY:

0.971

AC XY:

72268

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.895

AC:

37175

AN:

41542

American (AMR)

AF:

0.987

AC:

15099

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5176

AN:

5178

South Asian (SAS)

AF:

1.00

AC:

4816

AN:

4818

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68022

AN:

68036

Other (OTH)

AF:

0.978

AC:

2069

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

221

443

664

886

1107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.991

Hom.:

126282

Bravo

AF:

0.965

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.901

AC:

3472

ESP6500EA

AF:

1.00

AC:

8248

ExAC

AF:

0.991

AC:

119721

Asia WGS

AF:

0.995

AC:

3460

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.9

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0025

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.026

T;T;T

MetaRNN

Benign

0.0000015

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.7

N;.;.

PhyloP100

1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

1.6

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.016

MPC

0.13

ClinPred

0.0071

GERP RS

-1.1

Varity_R

0.044

gMVP

0.31

Mutation Taster

=79/21

polymorphism

(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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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