6-112136188-C-T

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.3349G>A(p.Gly1117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,611,098 control chromosomes in the GnomAD database, including 440,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45980 hom., cov: 32)

Exomes 𝑓: 0.73 ( 394636 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.50

Publications

39 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=9.803636E-7).

BP6

Variant 6-112136188-C-T is Benign according to our data. Variant chr6-112136188-C-T is described in ClinVar as Benign. ClinVar VariationId is 44376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3 link	c.3349G>A	p.Gly1117Ser	missense_variant	Exon 25 of 39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 link	c.3349G>A	p.Gly1117Ser	missense_variant	Exon 25 of 39	1	NM_001105206.3	ENSP00000230538.7

Frequencies

GnomAD3 genomes

AF:

0.773

AC:

117540

AN:

151994

Hom.:

45922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.859

Gnomad AMI

AF:

0.731

Gnomad AMR

AF:

0.812

Gnomad ASJ

AF:

0.758

Gnomad EAS

AF:

0.864

Gnomad SAS

AF:

0.872

Gnomad FIN

AF:

0.734

Gnomad MID

AF:

0.682

Gnomad NFE

AF:

0.706

Gnomad OTH

AF:

0.764

GnomAD2 exomes

AF:

0.775

AC:

194311

AN:

250840

AF XY:

0.773

show subpopulations

Gnomad AFR exome

AF:

0.868

Gnomad AMR exome

AF:

0.873

Gnomad ASJ exome

AF:

0.765

Gnomad EAS exome

AF:

0.854

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.702

Gnomad OTH exome

AF:

0.753

GnomAD4 exome

AF:

0.733

AC:

1069192

AN:

1458986

Hom.:

394636

Cov.:

AF XY:

0.736

AC XY:

534390

AN XY:

726006

show subpopulations

African (AFR)

AF:

0.862

AC:

28819

AN:

33424

American (AMR)

AF:

0.866

AC:

38695

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.758

AC:

19795

AN:

26100

East Asian (EAS)

AF:

0.862

AC:

34157

AN:

39638

South Asian (SAS)

AF:

0.858

AC:

74024

AN:

86228

European-Finnish (FIN)

AF:

0.741

AC:

39501

AN:

53294

Middle Eastern (MID)

AF:

0.708

AC:

4076

AN:

5756

European-Non Finnish (NFE)

AF:

0.708

AC:

785068

AN:

1109562

Other (OTH)

AF:

0.747

AC:

45057

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13123

26247

39370

52494

65617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19832

39664

59496

79328

99160

<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:

0.774

AC:

117660

AN:

152112

Hom.:

45980

Cov.:

AF XY:

0.777

AC XY:

57746

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.860

AC:

35684

AN:

41514

American (AMR)

AF:

0.812

AC:

12411

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.758

AC:

2628

AN:

3468

East Asian (EAS)

AF:

0.864

AC:

4469

AN:

5172

South Asian (SAS)

AF:

0.872

AC:

4201

AN:

4820

European-Finnish (FIN)

AF:

0.734

AC:

7763

AN:

10570

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.707

AC:

48022

AN:

67970

Other (OTH)

AF:

0.766

AC:

1618

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1350

2701

4051

5402

6752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.732

Hom.:

174086

Bravo

AF:

0.778

ESP6500AA

AF:

0.858

AC:

3782

ESP6500EA

AF:

0.697

AC:

5990

ExAC

AF:

0.769

AC:

93360

Asia WGS

AF:

0.890

AC:

3092

AN:

3478

EpiCase

AF:

0.705

EpiControl

AF:

0.709

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 04, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1JJ

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Aug 19, 2021

Genome-Nilou Lab

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

0.055

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.0051

T;T;T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.019

T;.;.;T

MetaRNN

Benign

9.8e-7

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.5

PrimateAI

Benign

0.27

PROVEAN

Benign

1.4

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.53

T;T;T;T

Vest4

0.039

MPC

0.12

ClinPred

0.0088

GERP RS

5.9

gMVP

0.23

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over