rs6917763

chr6-112175309-C-Achr6-112175309-C-T

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.1357+4G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,590 control chromosomes in the GnomAD database, including 2,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.017 (1155 hom.)
• Consequence: LAMA4 NM_001105206.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002992
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.474

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=-0.49).
• BP6: Variant 6-112175309-C-A is Benign according to our data. Variant chr6-112175309-C-A is described in ClinVar as [Benign]. Clinvar id is 44343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112175309-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.1357+4G>T		splice_donor_region_variant, intron_variant		ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.1357+4G>T		splice_donor_region_variant, intron_variant		1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11074 AN: 152108 Hom.: 1093 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0272 AC: 6834 AN: 251202 Hom.: 475 AF XY: 0.0237 AC XY: 3223 AN XY: 135790

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0165 AC: 24170 AN: 1461364 Hom.: 1155 Cov.: 32 AF XY: 0.0159 AC XY: 11530 AN XY: 726994

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00706

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0729 AC: 11100 AN: 152226 Hom.: 1096 Cov.: 33 AF XY: 0.0704 AC XY: 5243 AN XY: 74452

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.0417

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0634

Alfa AF: 0.0264 Hom.: 249

Bravo AF: 0.0833

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 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	GeneDx	Jan 24, 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	Dec 01, 2011	This variant is considered to be benign based on its high population frequency ( rs6917763, 2.5%) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	2.2
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs6917763; hg19: chr6-112496511;