rs2072021

Positions:

• chr6-112191703-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.43

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]

ACMG classification

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	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	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.: 32

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

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.: 33 AF XY: 0.153 AC XY: 111311 AN XY: 727058

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.: 32 AF XY: 0.264 AC XY: 19632 AN XY: 74336

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

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Dilated cardiomyopathy 1JJ Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Other links and lift over

dbSNP: rs2072021; hg19: chr6-112512905; COSMIC: COSV57894063; COSMIC: COSV57894063;