6-112136181-G-C

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.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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P1119H) has been classified as Uncertain significance.

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

Publications

30 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 -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 Benign/Likely_benign. ClinVar VariationId is 44377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMA4	NM_001105206.3	MANE Select	c.3356C>G	p.Pro1119Arg	missense	Exon 25 of 39	NP_001098676.2
LAMA4	NM_001105207.3		c.3335C>G	p.Pro1112Arg	missense	Exon 25 of 39	NP_001098677.2
LAMA4	NM_002290.5		c.3335C>G	p.Pro1112Arg	missense	Exon 25 of 39	NP_002281.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.3356C>G	p.Pro1119Arg	missense	Exon 25 of 39	ENSP00000230538.7
LAMA4	ENST00000389463.9	TSL:1	c.3335C>G	p.Pro1112Arg	missense	Exon 25 of 39	ENSP00000374114.4
LAMA4	ENST00000522006.5	TSL:1	c.3335C>G	p.Pro1112Arg	missense	Exon 25 of 39	ENSP00000429488.1

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

GnomAD2 exomes

AF:

0.225

AC:

56499

AN:

250812

AF XY:

0.226

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 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

African (AFR)

AF:

0.141

AC:

4703

AN:

33396

American (AMR)

AF:

0.176

AC:

7871

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

7495

AN:

26092

East Asian (EAS)

AF:

0.338

AC:

13407

AN:

39634

South Asian (SAS)

AF:

0.158

AC:

13579

AN:

86204

European-Finnish (FIN)

AF:

0.180

AC:

9588

AN:

53232

Middle Eastern (MID)

AF:

0.213

AC:

1224

AN:

5756

European-Non Finnish (NFE)

AF:

0.262

AC:

290683

AN:

1108268

Other (OTH)

AF:

0.246

AC:

14819

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

12898

25796

38693

51591

64489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9738

19476

29214

38952

48690

<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:

0.216

AC:

32782

AN:

152118

Hom.:

3702

Cov.:

AF XY:

0.210

AC XY:

15627

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.147

AC:

6121

AN:

41526

American (AMR)

AF:

0.190

AC:

2898

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

1001

AN:

3470

East Asian (EAS)

AF:

0.340

AC:

1757

AN:

5168

South Asian (SAS)

AF:

0.165

AC:

792

AN:

4806

European-Finnish (FIN)

AF:

0.168

AC:

1782

AN:

10580

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.260

AC:

17655

AN:

67964

Other (OTH)

AF:

0.234

AC:

494

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1347

2694

4040

5387

6734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.218

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

Nov 22, 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.

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

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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).

Clinical Genetics, Academic Medical Center

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

Dilated cardiomyopathy 1JJ

Benign:4

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0019

MetaSVM

Uncertain

-0.080

PhyloP100

8.9

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.65

Sift

Benign

0.23

Sift4G

Benign

0.23

Vest4

0.45

MPC

0.59

ClinPred

0.030

GERP RS

5.9

gMVP

0.70

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over