rs144686314

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_144670.6(A2ML1):c.3676_3677delGC(p.Ala1226GlnfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0475 in 1,613,182 control chromosomes in the GnomAD database, including 2,054 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1226A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.036 ( 134 hom., cov: 33)

Exomes 𝑓: 0.049 ( 1920 hom. )

Consequence

A2ML1
NM_144670.6 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 1.20

Publications

11 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 -16 ACMG points.

BP6

Variant 12-8863966-GGC-G is Benign according to our data. Variant chr12-8863966-GGC-G is described in ClinVar as Benign. ClinVar VariationId is 413822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
A2ML1	NM_144670.6 link	c.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift_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.3676_3677delGC	p.Ala1226GlnfsTer34	frameshift_variant	Exon 29 of 36	1	NM_144670.6	ENSP00000299698.7	A8K2U0-1
A2ML1	ENST00000541459.5 link	c.2326_2327delGC	p.Ala776GlnfsTer34	frameshift_variant	Exon 18 of 25	2		ENSP00000443174.1	H0YGG5
A2ML1	ENST00000539547.5 link	c.2203_2204delGC	p.Ala735GlnfsTer34	frameshift_variant	Exon 18 of 25	2		ENSP00000438292.1	A8K2U0-2
ENSG00000282022	ENST00000631830.1 link	n.322-5692_322-5691delGC		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0359

AC:

5470

AN:

152158

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0626

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0514

Gnomad OTH

AF:

0.0455

GnomAD2 exomes

AF:

0.0432

AC:

10760

AN:

249188

AF XY:

0.0459

show subpopulations

Gnomad AFR exome

AF:

0.00936

Gnomad AMR exome

AF:

0.0285

Gnomad ASJ exome

AF:

0.0635

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0513

GnomAD4 exome

AF:

0.0487

AC:

71145

AN:

1460906

Hom.:

1920

AF XY:

0.0496

AC XY:

36049

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.00921

AC:

308

AN:

33456

American (AMR)

AF:

0.0293

AC:

1309

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0624

AC:

1631

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0687

AC:

5921

AN:

86186

European-Finnish (FIN)

AF:

0.0317

AC:

1695

AN:

53398

Middle Eastern (MID)

AF:

0.0846

AC:

432

AN:

5106

European-Non Finnish (NFE)

AF:

0.0513

AC:

57032

AN:

1111914

Other (OTH)

AF:

0.0466

AC:

2812

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3136

6272

9407

12543

15679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2094

4188

6282

8376

10470

<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:

0.0359

AC:

5468

AN:

152276

Hom.:

134

Cov.:

AF XY:

0.0351

AC XY:

2617

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0106

AC:

441

AN:

41556

American (AMR)

AF:

0.0358

AC:

547

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

215

AN:

3468

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0633

AC:

305

AN:

4818

European-Finnish (FIN)

AF:

0.0302

AC:

320

AN:

10612

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0514

AC:

3495

AN:

68026

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

267

534

800

1067

1334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0458

Hom.:

Bravo

AF:

0.0346

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0537

EpiControl

AF:

0.0567

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24896146) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Otitis media

Uncertain:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:1

Aug 12, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: A2ML1 c.3676_3677delGC (p.Ala1226GlnfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, the variant allele was found at a frequency of 0.043 in 249188 control chromosomes, predominantly at a frequency of 0.068 within the South Asian subpopulation in the gnomAD database, including 87 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17000-folds over the estimated maximal expected allele frequency for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=157/43

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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