rs137893207

chr6-112158876-G-Achr6-112158876-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001105206.3(LAMA4):c.1673C>T(p.Ala558Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,605,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A558A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 2.53

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055383027).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.1673C>T	p.Ala558Val	missense_variant	14/39	ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.1673C>T	p.Ala558Val	missense_variant	14/39	1	NM_001105206.3	A1
	ENST00000585373.5	n.414+912G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000759 AC: 19 AN: 250312 Hom.: 0 AF XY: 0.0000887 AC XY: 12 AN XY: 135304

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000580

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000305 AC: 443 AN: 1453470 Hom.: 0 Cov.: 28 AF XY: 0.000278 AC XY: 201 AN XY: 723638

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74348

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2019	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by several other clinical laboratories (ClinVar Variant ID#194372; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2017	The p.Ala551Val variant (rs137893207) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 194372). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.029% (identified in 7 out of 23,984 chromosomes). The alanine at codon 551 is weakly conserved considering 12 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on LAMA4 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Ala551Val variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	LAMA4: BP4, BS2 -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 12, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Ala551Val var iant in LAMA4 has not been previously reported in individuals with cardiomyopath y, but has been identified in 6/62116 European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs137893207). Alanin e (Ala) at position 551 is not conserved in evolutionarily distant species with 7 reptiles and birds having a valine (Val) at that position, raising the possibi lity that this change may be tolerated. Other computational prediction tools sug gest that the p.Ala551Val variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala551Val variant is uncertain, these data sugges t that it is more likely to be benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 15, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LAMA4 p.Ala551Val Given the weak gene-phenotype evidence, the lack of case data and presence in unselected individuals (albeit rare), we consider this variant a variant of uncertain significance. LAMA4 variants have been reported in association with DCM, however only minimal evidence is available. Knoll et al (2007) identified LAMA4 as a candidate gene after a zebrafish screen then sequenced in patients with severe DCM and found a missense variant and a nonsense variant. We have not evaluated the strength of this evidence. This variant is novel. The variant was reported online in 8 of 57,245 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). Specifically, the variant was observed in 6 of 31,058 European individuals, 1 of 5057 African individuals, and 1 of 5477 Latino individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Dilated cardiomyopathy 1JJ Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2023	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 194372). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs137893207, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 551 of the LAMA4 protein (p.Ala551Val). -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 23, 2016

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2023

The p.A551V variant (also known as c.1652C>T), located in coding exon 13 of the LAMA4 gene, results from a C to T substitution at nucleotide position 1652. The alanine at codon 551 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Benign	0.74
DEOGEN2	Benign	0.0071	T;T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.86	D;.;.;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.55	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.17	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.14
MVP		0.20
MPC		0.12
ClinPred		0.042	T
GERP RS		5.7
gMVP		0.29

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: rs137893207; hg19: chr6-112480078; COSMIC: COSV57897455; COSMIC: COSV57897455;