chr6-112114135-C-T

Position:

• chr6-112114135-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001105206.3(LAMA4):​c.5267G>A​(p.Gly1756Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.87

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.5267G>A	p.Gly1756Glu	missense_variant	38/39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.5267G>A	p.Gly1756Glu	missense_variant	38/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2017

The p.Gly1749Glu variant in LAMA4 has not been previously reported in individual s with cardiomyopathy, but has been identified in 1/111448 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; d bSNP rs782244308). Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, t he clinical significance of the p.Gly1749Glu variant is uncertain. -

Dilated cardiomyopathy 1JJ Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 517367). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs782244308, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1749 of the LAMA4 protein (p.Gly1749Glu). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2023

The p.G1749E variant (also known as c.5246G>A), located in coding exon 37 of the LAMA4 gene, results from a G to A substitution at nucleotide position 5246. The glycine at codon 1749 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;.;.;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.95
MutPred		0.55		Gain of sheet (P = 0.0477);.;.;.;
MVP		0.95
MPC		0.65
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.86

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: rs782244308; hg19: chr6-112435338; COSMIC: COSV57906130;