rs78871662

Variant names:

Variant summary

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

The NM_001105206.3(LAMA4):c.196-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,553,406 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 27 hom., cov: 33)

Exomes 𝑓: 0.020 ( 362 hom. )

Consequence

LAMA4
NM_001105206.3 intron

Scores

Splicing: ADA: 0.009147

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.782

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 (BayesDel_noAF=-0.64).

BP6

Variant 6-112216481-A-G is Benign according to our data. Variant chr6-112216481-A-G is described in ClinVar as [Benign]. Clinvar id is 44354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112216481-A-G is described in Lovd as [Benign]. Variant chr6-112216481-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3 link	c.196-12T>C		intron_variant	Intron 2 of 38	ENST00000230538.12	NP_001098676.2	Q16363A0A0A0MQS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 link	c.196-12T>C		intron_variant	Intron 2 of 38	1	NM_001105206.3	ENSP00000230538.7		A0A0A0MQS9

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2510

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00528

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.0377

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0216

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0189

AC:

4749

AN:

250622

Hom.:

AF XY:

0.0200

AC XY:

2707

AN XY:

135442

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0322

Gnomad EAS exome

AF:

0.000436

Gnomad SAS exome

AF:

0.0205

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0201

AC:

28231

AN:

1401068

Hom.:

362

Cov.:

AF XY:

0.0204

AC XY:

14275

AN XY:

701038

show subpopulations

Gnomad4 AFR exome

AF:

0.00573

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0206

Gnomad4 FIN exome

AF:

0.0212

Gnomad4 NFE exome

AF:

0.0207

Gnomad4 OTH exome

AF:

0.0234

GnomAD4 genome

AF:

0.0164

AC:

2505

AN:

152338

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1243

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00529

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.0377

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.0209

Gnomad4 NFE

AF:

0.0216

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0230

Hom.:

Bravo

AF:

0.0155

Asia WGS

AF:

0.0160

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 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. -

Jul 29, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

196-12T>C in intron 2 of LAMA4: This variant is not expected to have clinical si gnificance because it has been identified in 2% (143/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs78871662). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1JJ

Benign:3

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0091

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.74

Position offset: 48

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