12-8847640-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_144670.6(A2ML1):c.1775G>T(p.Arg592Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,613,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R592W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.07

Publications

13 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-8847640-G-T is Benign according to our data. Variant chr12-8847640-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203521.

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.1775G>T	p.Arg592Leu	missense_variant	Exon 15 of 36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 link	c.1775G>T	p.Arg592Leu	missense_variant	Exon 15 of 36	1	NM_144670.6	ENSP00000299698.7

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000382

AC:

AN:

248816

AF XY:

0.000341

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000655

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000670

AC:

979

AN:

1461282

Hom.:

Cov.:

AF XY:

0.000623

AC XY:

453

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33454

American (AMR)

AF:

0.000224

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000822

AC:

914

AN:

1111710

Other (OTH)

AF:

0.000729

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000394

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.000338

AC:

AN:

41438

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68020

Other (OTH)

AF:

0.00144

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00000945

Hom.:

Bravo

AF:

0.000419

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.000604

AC:

ExAC

AF:

0.000430

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000950

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Apr 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Expression in a zebrafish model led to developmental defects including broad forehead, blunted face, and cardiac malformations (Vissers et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24939586, 27942422)

Mar 01, 2015

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 592 of the A2ML1 protein (p.Arg592Leu). This variant is present in population databases (rs200673370, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 24939586, 33082526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203521). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects A2ML1 function (PMID: 24939586). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not specified

Uncertain:1

Jun 01, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: A2ML1 c.1775G>T (p.Arg592Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 248816 control chromosomes. The observed variant frequency is approximately 95 fold of the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome And Related Conditions phenotype (4e-06), strongly suggesting that the variant is benign. However, c.1775G>T has been reported in the literature in one multi-generation family affected with Noonan Syndrome (Vissers_2015). Co-segregation was seen in all affected family members. This variant has also been reported in one patient with Kabuki syndrome who also carries a de novo pathogenic variant (KMT2D c.4148G>A/p.C1383Y, Long_2016). One functional study in Zebrafish showed that p.S600L (mimicing human p.R592L) caused developmental defects (Vissers_2015). Since the wild-type amino acid in Zebrafish is different to human A2ML1, this result does not allow convincing conclusions about the variant effect. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

M;.;.;.

PhyloP100

2.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Vest4

0.82

ClinPred

0.24

GERP RS

2.7

Varity_R

0.38

gMVP

0.62

Mutation Taster

=12/88

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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