6-112114061-T-G

Position:

• chr6-112114061-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001105206.3(LAMA4):​c.5326+15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,609,574 control chromosomes in the GnomAD database, including 55,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4634 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50568 hom.)
• Consequence: LAMA4 NM_001105206.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.109

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-112114061-T-G is Benign according to our data. Variant chr6-112114061-T-G is described in ClinVar as [Benign]. Clinvar id is 44405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112114061-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.5326+15A>C		intron_variant		ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.5326+15A>C		intron_variant		1	NM_001105206.3	ENSP00000230538.7

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37685 AN: 151848 Hom.: 4635 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.238 AC: 59739 AN: 250856 Hom.: 7525 AF XY: 0.236 AC XY: 31992 AN XY: 135546

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.332

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.260 AC: 378333 AN: 1457608 Hom.: 50568 Cov.: 35 AF XY: 0.256 AC XY: 185733 AN XY: 725394

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.248 AC: 37706 AN: 151966 Hom.: 4634 Cov.: 32 AF XY: 0.243 AC XY: 18043 AN XY: 74282

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.261

Alfa AF: 0.260 Hom.: 978

Bravo AF: 0.251

Asia WGS AF: 0.238 AC: 825 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 28, 2011	This variant is classified as benign because it is located in the intron outside the splice consensus and occurs in the general population at a frequency of >1% (rs3734290). -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Dilated cardiomyopathy 1JJ Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.52

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: rs3734290; hg19: chr6-112435264; COSMIC: COSV57893530;