rs142794811

Positions:

chr12-8857942-G-GT

Variant summary

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

The NM_144670.6(A2ML1):c.3108-3dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,613,820 control chromosomes in the GnomAD database, including 617 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 49 hom., cov: 31)

Exomes 𝑓: 0.0082 ( 568 hom. )

Consequence

A2ML1
NM_144670.6 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.517

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 12-8857942-G-GT is Benign according to our data. Variant chr12-8857942-G-GT is described in ClinVar as [Benign]. Clinvar id is 252784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.3108-3dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000299698.12

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.3108-3dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_144670.6	P1	A8K2U0-1
A2ML1	ENST00000539547.5 linkuse as main transcript	c.1635-3dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2			A8K2U0-2
A2ML1	ENST00000541459.5 linkuse as main transcript	c.1758-3dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2

Frequencies

GnomAD3 genomes

AF:

0.00939

AC:

1428

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0426

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0850

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0255

AC:

6349

AN:

249196

Hom.:

409

AF XY:

0.0209

AC XY:

2820

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.0943

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.00525

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.00819

AC:

11964

AN:

1461586

Hom.:

568

Cov.:

AF XY:

0.00766

AC XY:

5569

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.00195

Gnomad4 EAS exome

AF:

0.0945

Gnomad4 SAS exome

AF:

0.00361

Gnomad4 FIN exome

AF:

0.00455

Gnomad4 NFE exome

AF:

0.00191

Gnomad4 OTH exome

AF:

0.00772

GnomAD4 genome

AF:

0.00939

AC:

1430

AN:

152234

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

782

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.0426

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0856

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.00585

Gnomad4 NFE

AF:

0.00196

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: A2ML1 c.3108-3dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.024 in 280586 control chromosomes in the gnomAD database, including 417 homozygotes. The observed variant frequency is approximately 5937-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 benign. Three ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Otitis media, susceptibility to

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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