chr6-112120302-T-C

Position:

chr6-112120302-T-C

Variant summary

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

The ENST00000230538.12(LAMA4):c.4646A>G(p.Asn1549Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00283 in 1,613,886 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1549I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 70 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 55 hom. )

Consequence

LAMA4
ENST00000230538.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.27

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=0.009806722).

BP6

Variant 6-112120302-T-C is Benign according to our data. Variant chr6-112120302-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112120302-T-C is described in Lovd as [Benign]. Variant chr6-112120302-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 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.4646A>G	p.Asn1549Ser	missense_variant	33/39	ENST00000230538.12	NP_001098676.2
LOC107986633	XR_001744299.2 linkuse as main transcript	n.439+3875T>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.4646A>G	p.Asn1549Ser	missense_variant	33/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2342

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0544

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00392

AC:

984

AN:

250862

Hom.:

AF XY:

0.00288

AC XY:

390

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.0549

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00151

AC:

2214

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.0536

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000827

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.0154

AC:

2347

AN:

152332

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1082

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0544

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.0165

ESP6500AA

AF:

0.0497

AC:

219

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00485

AC:

589

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2014	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2012	35/2000 chr (1000 Genomes project) - MAF=0.016 -

Dilated cardiomyopathy 1JJ

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;.;.;D

MetaRNN

Benign

0.0098

T;T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Uncertain

0.32

Sift

Benign

0.082

T;T;T;T

Sift4G

Benign

0.079

T;T;T;T

Vest4

0.30

MVP

0.68

MPC

0.13

ClinPred

0.056

GERP RS

2.1

gMVP

0.31

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