chr12-8863966-GGC-G

Position:

chr12-8863966-GGC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_144670.6(A2ML1):c.3676_3677del(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 (★★). 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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 413822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8863966-GGC-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.3676_3677del	p.Ala1226GlnfsTer34	frameshift_variant	29/36	ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.3676_3677del	p.Ala1226GlnfsTer34	frameshift_variant	29/36	1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
	ENST00000631830.1 linkuse as main transcript	n.322-5692_322-5691del		intron_variant, non_coding_transcript_variant		3
A2ML1	ENST00000539547.5 linkuse as main transcript	c.2203_2204del	p.Ala735GlnfsTer34	frameshift_variant	18/25	2		ENSP00000438292		A8K2U0-2
A2ML1	ENST00000541459.5 linkuse as main transcript	c.2326_2327del	p.Ala776GlnfsTer34	frameshift_variant	18/25	2		ENSP00000443174

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

GnomAD3 exomes

AF:

0.0432

AC:

10760

AN:

249188

Hom.:

306

AF XY:

0.0459

AC XY:

6211

AN XY:

135238

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 SAS exome

AF:

0.0680

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

Gnomad4 AFR exome

AF:

0.00921

Gnomad4 AMR exome

AF:

0.0293

Gnomad4 ASJ exome

AF:

0.0624

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0687

Gnomad4 FIN exome

AF:

0.0317

Gnomad4 NFE exome

AF:

0.0513

Gnomad4 OTH exome

AF:

0.0466

GnomAD4 genome

AF:

0.0359

AC:

5468

AN:

152276

Hom.:

134

Cov.:

AF XY:

0.0351

AC XY:

2617

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.0358

Gnomad4 ASJ

AF:

0.0620

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0633

Gnomad4 FIN

AF:

0.0302

Gnomad4 NFE

AF:

0.0514

Gnomad4 OTH

AF:

0.0450

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2018	This variant is associated with the following publications: (PMID: 24896146) -

Otitis media

Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 12, 2019

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over