12-8835642-G-C

Position:

chr12-8835642-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144670.6(A2ML1):c.619G>C(p.Gly207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,080 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. G207G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.026 ( 173 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 162 hom. )

Consequence

A2ML1
NM_144670.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.222

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015576482).

BP6

Variant 12-8835642-G-C is Benign according to our data. Variant chr12-8835642-G-C is described in ClinVar as [Benign]. Clinvar id is 120255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8835642-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0868 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.619G>C	p.Gly207Arg	missense_variant	6/36	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.619G>C	p.Gly207Arg	missense_variant	6/36	1	NM_144670.6	ENSP00000299698	P1	A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3928

AN:

152118

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00654

AC:

1632

AN:

249422

Hom.:

AF XY:

0.00450

AC XY:

609

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.0902

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00271

AC:

3956

AN:

1461844

Hom.:

162

Cov.:

AF XY:

0.00227

AC XY:

1653

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0915

Gnomad4 AMR exome

AF:

0.00577

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000215

Gnomad4 OTH exome

AF:

0.00556

GnomAD4 genome

AF:

0.0258

AC:

3932

AN:

152236

Hom.:

173

Cov.:

AF XY:

0.0250

AC XY:

1859

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0892

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.0294

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0811

AC:

327

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.00798

AC:

965

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2017	Variant summary: The A2ML1 c.619G>C (p.Gly207Arg) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 956/120716 control chromosomes (44 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.088193 (865/9808). This frequency is about 22048 times the estimated maximal expected allele frequency of a pathogenic A2ML1 variant (0.000004), thus it is a common benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory (via ClinVar) has classified this variant as benign. Taken together, this variant is classified as benign. -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2016	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.74

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

REVEL

Benign

0.025

Sift

Benign

0.12

Sift4G

Benign

0.41

Polyphen

0.027

Vest4

0.28

MVP

0.040

MPC

0.15

ClinPred

0.0014

GERP RS

0.99

Varity_R

0.12

gMVP

0.54

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

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