NM_144670.6:c.861C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_144670.6(A2ML1):c.861C>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,612,544 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. D287G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 8 hom., cov: 32)

Exomes 𝑓: 0.010 ( 85 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0420

Publications

12 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00356704).

BP6

Variant 12-8838341-C-A is Benign according to our data. Variant chr12-8838341-C-A is described in ClinVar as Benign. ClinVar VariationId is 120256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1071 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144670.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	NM_144670.6	MANE Select	c.861C>A	p.Asp287Glu	missense	Exon 9 of 36	NP_653271.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2ML1	ENST00000299698.12	TSL:1 MANE Select	c.861C>A	p.Asp287Glu	missense	Exon 9 of 36	ENSP00000299698.7

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1070

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00770

AC:

1916

AN:

248948

AF XY:

0.00768

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00380

Gnomad ASJ exome

AF:

0.0306

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00557

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00630

GnomAD4 exome

AF:

0.0102

AC:

14894

AN:

1460254

Hom.:

Cov.:

AF XY:

0.00988

AC XY:

7176

AN XY:

726430

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33446

American (AMR)

AF:

0.00398

AC:

178

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0278

AC:

727

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00164

AC:

141

AN:

86004

European-Finnish (FIN)

AF:

0.00547

AC:

292

AN:

53398

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0115

AC:

12824

AN:

1110854

Other (OTH)

AF:

0.0107

AC:

643

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

666

1331

1997

2662

3328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.00703

AC:

1071

AN:

152290

Hom.:

Cov.:

AF XY:

0.00655

AC XY:

488

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41562

American (AMR)

AF:

0.00556

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

730

AN:

68018

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00914

Hom.:

Bravo

AF:

0.00718

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00154

AC:

ESP6500EA

AF:

0.0142

AC:

118

ExAC

AF:

0.00744

AC:

899

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00922

EpiControl

AF:

0.0108

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Benign

0.075

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

-0.042

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.0

REVEL

Benign

0.034

Sift

Benign

0.040

Sift4G

Benign

0.16

Polyphen

0.78

Vest4

0.32

MutPred

0.29

Gain of sheet (P = 0.0827)

MVP

0.17

MPC

0.19

ClinPred

0.0050

GERP RS

2.9

Varity_R

0.13

gMVP

0.75

Mutation Taster

=86/14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over