chr12-8835644-T-C

Position:

chr12-8835644-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_144670.6(A2ML1):c.621T>C(p.Gly207Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,614,176 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 36 hom. )

Consequence

A2ML1
NM_144670.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0700

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:

A2ML1 (HGNC:):

A2ML1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 12-8835644-T-C is Benign according to our data. Variant chr12-8835644-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 224925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-8835644-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00235 (3438/1461854) while in subpopulation MID AF= 0.0168 (97/5766). AF 95% confidence interval is 0.0151. There are 36 homozygotes in gnomad4_exome. There are 2051 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2ML1	NM_144670.6 linkuse as main transcript	c.621T>C	p.Gly207Gly	synonymous_variant	6/36	ENST00000299698.12	NP_653271.3	B3KVV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2ML1	ENST00000299698.12 linkuse as main transcript	c.621T>C	p.Gly207Gly	synonymous_variant	6/36	1	NM_144670.6	ENSP00000299698.7		A8K2U0-1

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

397

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00376

AC:

937

AN:

249434

Hom.:

AF XY:

0.00449

AC XY:

608

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00413

GnomAD4 exome

AF:

0.00235

AC:

3438

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2051

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00846

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.00259

AC:

395

AN:

152322

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00191

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

A2ML1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

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

-0.64

CADD

Benign

8.0

DANN

Benign

0.72

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