chr6-112165195-G-A

Position:

chr6-112165195-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001105206.3(LAMA4):c.1633C>T(p.Arg545Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,611,554 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.15

Variant links:

Genes affected

LAMA4 (HGNC:6484): (laminin subunit alpha 4) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the alpha chain isoform laminin, alpha 4. The domain structure of alpha 4 is similar to that of alpha 3, both of which resemble truncated versions of alpha 1 and alpha 2, in that approximately 1,200 residues at the N-terminus (domains IV, V and VI) have been lost. Laminin, alpha 4 contains the C-terminal G domain which distinguishes all alpha chains from the beta and gamma chains. The RNA analysis from adult and fetal tissues revealed developmental regulation of expression, however, the exact function of laminin, alpha 4 is not known. Tissue-specific utilization of alternative polyA-signal has been described in literature. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

LAMA4 links:

ENSG00000237234 (HGNC:):

ENSG00000237234 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015549004).

BP6

Variant 6-112165195-G-A is Benign according to our data. Variant chr6-112165195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112165195-G-A is described in Lovd as [Benign]. Variant chr6-112165195-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3 link	c.1633C>T	p.Arg545Cys	missense_variant	13/39	ENST00000230538.12	NP_001098676.2	Q16363A0A0A0MQS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 link	c.1633C>T	p.Arg545Cys	missense_variant	13/39	1	NM_001105206.3	ENSP00000230538.7		A0A0A0MQS9

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00147

AC:

369

AN:

251368

Hom.:

AF XY:

0.00143

AC XY:

194

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00183

AC:

2675

AN:

1459260

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1371

AN XY:

726122

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.000650

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00134

AC:

204

AN:

152294

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00161

AC:

196

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	LAMA4: BP4, BS1, BS2 -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2015	p.Arg538Cys in exon 13 of LAMA4: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (19/6614) of Finnish chromoso mes and 0.2% (153/66734) of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs138153075). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1JJ

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Hypertrophic cardiomyopathy;C0042514:Ventricular tachycardia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 31, 2019

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 23, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2020

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

T;T;T;T

Eigen

Benign

-0.081

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.87

D;.;.;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Benign

0.19

Sift

Benign

0.093

T;T;T;T

Sift4G

Uncertain

0.034

D;D;D;D

Vest4

0.50

MVP

0.44

MPC

0.56

ClinPred

0.025

GERP RS

3.2

gMVP

0.22

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