6-112136181-G-C

Position:

chr6-112136181-G-C

Variant summary

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

The NM_001105206.3(LAMA4):c.3356C>G(p.Pro1119Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,609,616 control chromosomes in the GnomAD database, including 50,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.22 ( 3702 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46688 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 8.85

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:

LOC107986633 (HGNC:):

LOC107986633 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=0.0019278228).

BP6

Variant 6-112136181-G-C is Benign according to our data. Variant chr6-112136181-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 44377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112136181-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.3356C>G	p.Pro1119Arg	missense_variant	25/39	ENST00000230538.12	NP_001098676.2
LOC107986633	XR_001744299.2 linkuse as main transcript	n.440-19139G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.3356C>G	p.Pro1119Arg	missense_variant	25/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32774

AN:

152000

Hom.:

3702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.340

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.168

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.260

Gnomad OTH

AF:

0.233

GnomAD3 exomes

AF:

0.225

AC:

56499

AN:

250812

Hom.:

6838

AF XY:

0.226

AC XY:

30627

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.351

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.173

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.241

GnomAD4 exome

AF:

0.249

AC:

363369

AN:

1457498

Hom.:

46688

Cov.:

AF XY:

0.247

AC XY:

179114

AN XY:

725272

show subpopulations

Gnomad4 AFR exome

AF:

0.141

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.287

Gnomad4 EAS exome

AF:

0.338

Gnomad4 SAS exome

AF:

0.158

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.262

Gnomad4 OTH exome

AF:

0.246

GnomAD4 genome

AF:

0.216

AC:

32782

AN:

152118

Hom.:

3702

Cov.:

AF XY:

0.210

AC XY:

15627

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.147

Gnomad4 AMR

AF:

0.190

Gnomad4 ASJ

AF:

0.288

Gnomad4 EAS

AF:

0.340

Gnomad4 SAS

AF:

0.165

Gnomad4 FIN

AF:

0.168

Gnomad4 NFE

AF:

0.260

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.218

Hom.:

1330

Bravo

AF:

0.218

TwinsUK

AF:

0.259

AC:

959

ALSPAC

AF:

0.255

AC:

981

ESP6500AA

AF:

0.147

AC:

649

ESP6500EA

AF:

0.260

AC:

2239

ExAC

AF:

0.225

AC:

27305

Asia WGS

AF:

0.236

AC:

818

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.265

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	Pro1112Arg in exon 25 of LAMA4: This variant is not expected to have clinical s ignificance because it has been identified in 26% (1825/7020) of European Americ an chromosomes and 15% (552/3738) of African American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs1050349). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1JJ

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

T;T;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;.;.;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Uncertain

-0.080

MutationTaster

Benign

5.6e-7

P;P;P;P

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.23

T;D;D;D

Sift4G

Benign

0.23

T;T;T;T

Vest4

0.45

MPC

0.59

ClinPred

0.030

GERP RS

5.9

gMVP

0.70

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