12-8854772-C-A

Position:

chr12-8854772-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000299698.12(A2ML1):c.2713-8C>A 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 0.00138 in 1,614,130 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 11 hom. )

Consequence

A2ML1
ENST00000299698.12 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.002972

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.477

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 12-8854772-C-A is Benign according to our data. Variant chr12-8854772-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241896.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr12-8854772-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.2713-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000299698.12	NP_653271.3

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.2713-8C>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1
A2ML1	ENST00000539547.5 linkuse as main transcript	c.1240-8C>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2		ENSP00000438292		A8K2U0-2
A2ML1	ENST00000541459.5 linkuse as main transcript	c.1363-8C>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	2		ENSP00000443174

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00172

AC:

429

AN:

249404

Hom.:

AF XY:

0.00168

AC XY:

228

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.000990

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00130

AC:

1907

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

938

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.000986

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152306

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0178

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000747

Hom.:

Bravo

AF:

0.00100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2018	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. -

Otitis media

Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Otitis media, susceptibility to

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Santos-Cortez Lab, University of Colorado School of Medicine

Apr 25, 2019

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 22, 2019

Variant summary: A2ML1 c.2713-8C>A 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. 5/5 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 0.0017 in 249404 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 430-fold over the estimated maximal allele frequency expected for a pathogenic variant in A2ML1 causing Noonan Syndrome phenotype (4e-06), strongly suggesting that the variant is benign. Co-occurrence with another pathogenic variant has been reported (PTPN11 c.923A>C, p.N308T; internal sample), providing supporting evidence for a benign role. To our knowledge, there are no reports of c.2713-8C>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function in the literature. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories cited the variant as benign and one cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

A2ML1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.5

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.040

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