rs41289902

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001105206.3(LAMA4):c.3239G>A(p.Arg1080Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,076 control chromosomes in the GnomAD database, including 157 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. R1080R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 5 hom., cov: 33)

Exomes 𝑓: 0.012 ( 152 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 7.38

Publications

19 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:

LOC107986633 (HGNC:):

LOC107986633 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017812014).

BP6

Variant 6-112139163-C-T is Benign according to our data. Variant chr6-112139163-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3 link	c.3239G>A	p.Arg1080Gln	missense_variant	Exon 24 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.3239G>A	p.Arg1080Gln	missense_variant	Exon 24 of 39	1	NM_001105206.3	ENSP00000230538.7		A0A0A0MQS9

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1522

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.0103

AC:

2597

AN:

251242

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00763

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0123

AC:

17934

AN:

1461802

Hom.:

152

Cov.:

AF XY:

0.0120

AC XY:

8730

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33478

American (AMR)

AF:

0.00762

AC:

341

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00681

AC:

178

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00204

AC:

176

AN:

86258

European-Finnish (FIN)

AF:

0.0231

AC:

1235

AN:

53420

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0138

AC:

15297

AN:

1111926

Other (OTH)

AF:

0.0105

AC:

633

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

931

1862

2793

3724

4655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.00999

AC:

1521

AN:

152274

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

770

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41572

American (AMR)

AF:

0.0104

AC:

159

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0244

AC:

259

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

959

AN:

68012

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0124

Hom.:

Bravo

AF:

0.00884

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00999

AC:

1213

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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

- -

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

- -

Jan 31, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg1073Gln in exon 24 of LAMA4: This variant is classified as benign based on i ts high frequency in the general population (rs41289902; http://evs.gs.washingto n.edu/EVS/). -

Feb 06, 2014

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. -

Jun 11, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1JJ

Benign:5

Sep 21, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jun 27, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMA4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.031

T;T;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;.;.;D

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

0.13

PhyloP100

7.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.85

N;N;N;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.059

T;T;T;T

Vest4

0.97

MPC

0.61

ClinPred

0.047

GERP RS

6.0

gMVP

0.74

Mutation Taster

=97/3

polymorphism

(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