rs2072021

Positions:

chr6-112191703-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001105206.3(LAMA4):c.651C>T(p.Thr217=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,613,544 control chromosomes in the GnomAD database, including 29,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 7687 hom., cov: 32)

Exomes 𝑓: 0.15 ( 21733 hom. )

Consequence

LAMA4
NM_001105206.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.43

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 6-112191703-G-A is Benign according to our data. Variant chr6-112191703-G-A is described in ClinVar as [Benign]. Clinvar id is 44409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112191703-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.651C>T	p.Thr217=	synonymous_variant	6/39	ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.651C>T	p.Thr217=	synonymous_variant	6/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39717

AN:

151948

Hom.:

7671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.289

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.196

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.131

Gnomad OTH

AF:

0.222

GnomAD3 exomes

AF:

0.189

AC:

47437

AN:

250782

Hom.:

6081

AF XY:

0.186

AC XY:

25205

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.556

Gnomad AMR exome

AF:

0.133

Gnomad ASJ exome

AF:

0.158

Gnomad EAS exome

AF:

0.278

Gnomad SAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.191

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.151

AC:

220855

AN:

1461478

Hom.:

21733

Cov.:

AF XY:

0.153

AC XY:

111311

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.558

Gnomad4 AMR exome

AF:

0.138

Gnomad4 ASJ exome

AF:

0.159

Gnomad4 EAS exome

AF:

0.362

Gnomad4 SAS exome

AF:

0.244

Gnomad4 FIN exome

AF:

0.186

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.170

GnomAD4 genome

AF:

0.262

AC:

39786

AN:

152066

Hom.:

7687

Cov.:

AF XY:

0.264

AC XY:

19632

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.541

Gnomad4 AMR

AF:

0.170

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.289

Gnomad4 SAS

AF:

0.244

Gnomad4 FIN

AF:

0.196

Gnomad4 NFE

AF:

0.131

Gnomad4 OTH

AF:

0.223

Alfa

AF:

0.150

Hom.:

4035

Bravo

AF:

0.267

Asia WGS

AF:

0.245

AC:

852

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1JJ

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.2

DANN

Benign

0.88

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

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