rs70940811

Positions:

• chr6-112130993-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001105206.3(LAMA4):​c.3943G>A​(p.Val1315Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,042 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.00800

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]

LOC107986633 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030601919).
• BP6: Variant 6-112130993-C-T is Benign according to our data. Variant chr6-112130993-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44380.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4}. Variant chr6-112130993-C-T is described in Lovd as [Benign]. Variant chr6-112130993-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.3943G>A	p.Val1315Ile	missense_variant	29/39	ENST00000230538.12
LOC107986633	XR_001744299.2	n.439+14566C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.3943G>A	p.Val1315Ile	missense_variant	29/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00127 AC: 319 AN: 250794 Hom.: 3 AF XY: 0.00114 AC XY: 154 AN XY: 135518

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000372 AC: 544 AN: 1460846 Hom.: 4 Cov.: 31 AF XY: 0.000377 AC XY: 274 AN XY: 726752

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00923

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74428

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0166

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.000710

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 05, 2012	Variant classified as Uncertain Significance - Favor Benign. The Val1308Ile vari ant (LAMA4) has been identified in 2/46 chromosomes from an Asian population, 7/ 2334 chromosomes from the 1000 Genomes population, and 1/3738 chromosomes from a broad but clinically unspecified African American cohort (http://evs.gs.washing ton.edu/EVS, dbSNP rs70940811). Valine (Val) residue at position 1308 is not con served among mammals, suggesting that a change may be tolerated. Computational t ools (PolyPhen2, SIFT, AlignGVGD) also predict this change to be benign although their accuracy is unknown. In summary, this variant is more likely benign but additional information is needed to fully assess its clinical significance. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2014	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 1JJ Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 23, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.7
DANN	Benign	0.72
DEOGEN2	Benign	0.015	T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.73	T;.;.;T
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.12
MVP		0.30
MPC		0.097
ClinPred		0.0038	T
GERP RS		-2.0
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs70940811; hg19: chr6-112452195; COSMIC: COSV57893577; COSMIC: COSV57893577;