6-112201651-G-A

Position:

chr6-112201651-G-A

Variant summary

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

The NM_001105206.3(LAMA4):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,122 control chromosomes in the GnomAD database, including 3,545 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.044 ( 219 hom., cov: 33)

Exomes 𝑓: 0.062 ( 3326 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.45

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:

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=0.006450653).

BP6

Variant 6-112201651-G-A is Benign according to our data. Variant chr6-112201651-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112201651-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0792 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.460C>T	p.Arg154Trp	missense_variant	5/39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes

AF:

0.0439

AC:

6673

AN:

152102

Hom.:

223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0410

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0863

Gnomad FIN

AF:

0.0370

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0660

Gnomad OTH

AF:

0.0469

GnomAD3 exomes

AF:

0.0522

AC:

13101

AN:

250976

Hom.:

502

AF XY:

0.0574

AC XY:

7788

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.00997

Gnomad AMR exome

AF:

0.0275

Gnomad ASJ exome

AF:

0.0399

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.0401

Gnomad NFE exome

AF:

0.0645

Gnomad OTH exome

AF:

0.0542

GnomAD4 exome

AF:

0.0624

AC:

91135

AN:

1460902

Hom.:

3326

Cov.:

AF XY:

0.0640

AC XY:

46547

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.0292

Gnomad4 ASJ exome

AF:

0.0389

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0970

Gnomad4 FIN exome

AF:

0.0403

Gnomad4 NFE exome

AF:

0.0664

Gnomad4 OTH exome

AF:

0.0612

GnomAD4 genome

AF:

0.0438

AC:

6666

AN:

152220

Hom.:

219

Cov.:

AF XY:

0.0430

AC XY:

3203

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0116

Gnomad4 AMR

AF:

0.0409

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0860

Gnomad4 FIN

AF:

0.0370

Gnomad4 NFE

AF:

0.0660

Gnomad4 OTH

AF:

0.0460

Alfa

AF:

0.0607

Hom.:

617

Bravo

AF:

0.0409

TwinsUK

AF:

0.0766

AC:

284

ALSPAC

AF:

0.0695

AC:

268

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.0649

AC:

558

ExAC

AF:

0.0530

AC:

6440

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0669

EpiControl

AF:

0.0684

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Sep 27, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Dilated cardiomyopathy 1JJ

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;T;T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

D;.;.;D;D

MetaRNN

Benign

0.0065

T;T;T;T;T

MetaSVM

Uncertain

-0.23

MutationTaster

Benign

0.90

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.1

D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;.

Vest4

0.48

MPC

0.58

ClinPred

0.036

GERP RS

4.2

gMVP

0.64

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