rs1860926

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2550C>A(p.Asp850Glu) 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 1,614,124 control chromosomes in the GnomAD database, including 797,374 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 0.97 ( 71161 hom., cov: 31)

Exomes 𝑓: 1.0 ( 726213 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.103

Publications

31 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=9.4884257E-7).

BP6

Variant 12-8852296-C-A is Benign according to our data. Variant chr12-8852296-C-A is described in ClinVar as Benign. ClinVar VariationId is 1169145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) 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.2550C>A	p.Asp850Glu	missense_variant	Exon 20 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.2550C>A	p.Asp850Glu	missense_variant	Exon 20 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.1200C>A	p.Asp400Glu	missense_variant	Exon 9 of 25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.1077C>A	p.Asp359Glu	missense_variant	Exon 9 of 25	2		ENSP00000438292.1	A8K2U0-2

Frequencies

GnomAD3 genomes

AF:

0.966

AC:

146898

AN:

152122

Hom.:

71113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.882

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.984

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.975

GnomAD2 exomes

AF:

0.992

AC:

247429

AN:

249514

AF XY:

0.994

show subpopulations

Gnomad AFR exome

AF:

0.882

Gnomad AMR exome

AF:

0.994

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:

0.996

GnomAD4 exome

AF:

0.997

AC:

1456877

AN:

1461884

Hom.:

726213

Cov.:

AF XY:

0.997

AC XY:

725076

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.880

AC:

29461

AN:

33480

American (AMR)

AF:

0.993

AC:

44427

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26136

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39697

AN:

39698

South Asian (SAS)

AF:

1.00

AC:

86242

AN:

86258

European-Finnish (FIN)

AF:

1.00

AC:

53414

AN:

53414

Middle Eastern (MID)

AF:

0.994

AC:

5734

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111844

AN:

1112010

Other (OTH)

AF:

0.992

AC:

59922

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

268

536

804

1072

1340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<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:

0.966

AC:

147001

AN:

152240

Hom.:

71161

Cov.:

AF XY:

0.966

AC XY:

71932

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.882

AC:

36602

AN:

41500

American (AMR)

AF:

0.984

AC:

15046

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5172

AN:

5172

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4828

European-Finnish (FIN)

AF:

1.00

AC:

10616

AN:

10616

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

68000

AN:

68036

Other (OTH)

AF:

0.975

AC:

2062

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

225

450

675

900

1125

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:

0.988

Hom.:

144012

Bravo

AF:

0.959

TwinsUK

AF:

1.00

AC:

3707

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.890

AC:

3510

ESP6500EA

AF:

1.00

AC:

8352

ExAC

AF:

0.990

AC:

119575

Asia WGS

AF:

0.990

AC:

3443

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

0.061

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.6

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.0026

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.076

T;T;T

MetaRNN

Benign

9.5e-7

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.2

N;.;.

PhyloP100

0.10

PrimateAI

Benign

0.38

PROVEAN

Benign

1.8

N;N;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.039

MutPred

0.30

Gain of ubiquitination at K852 (P = 0.1278);.;.;

MPC

0.097

ClinPred

0.00089

GERP RS

2.0

Varity_R

0.041

gMVP

0.11

Mutation Taster

=100/0

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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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