6-112201651-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. R154R) 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

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy 1JJ
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

LAMA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 44392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3 link	c.460C>T	p.Arg154Trp	missense_variant	Exon 5 of 39	ENST00000230538.12	NP_001098676.2	Q16363A0A0A0MQS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 link	c.460C>T	p.Arg154Trp	missense_variant	Exon 5 of 39	1	NM_001105206.3	ENSP00000230538.7		A0A0A0MQS9

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

GnomAD2 exomes

AF:

0.0522

AC:

13101

AN:

250976

AF XY:

0.0574

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 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

African (AFR)

AF:

0.0101

AC:

337

AN:

33446

American (AMR)

AF:

0.0292

AC:

1304

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

1015

AN:

26124

East Asian (EAS)

AF:

0.000277

AC:

AN:

39690

South Asian (SAS)

AF:

0.0970

AC:

8364

AN:

86228

European-Finnish (FIN)

AF:

0.0403

AC:

2154

AN:

53390

Middle Eastern (MID)

AF:

0.0821

AC:

473

AN:

5764

European-Non Finnish (NFE)

AF:

0.0664

AC:

73784

AN:

1111196

Other (OTH)

AF:

0.0612

AC:

3693

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

4225

8450

12674

16899

21124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2694

5388

8082

10776

13470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0438

AC:

6666

AN:

152220

Hom.:

219

Cov.:

AF XY:

0.0430

AC XY:

3203

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0116

AC:

480

AN:

41540

American (AMR)

AF:

0.0409

AC:

625

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.0860

AC:

414

AN:

4814

European-Finnish (FIN)

AF:

0.0370

AC:

392

AN:

10604

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0660

AC:

4491

AN:

68016

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

337

675

1012

1350

1687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0593

Hom.:

1188

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

Apr 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dilated cardiomyopathy 1JJ

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.5

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over