rs78871662

Positions:

• chr6-112216481-A-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.196-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,553,406 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 33)
  • Exomes 𝑓: 0.020 (362 hom.)
• Consequence: LAMA4 NM_001105206.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.009147
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.782

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=-0.64).
• BP6: Variant 6-112216481-A-G is Benign according to our data. Variant chr6-112216481-A-G is described in ClinVar as [Benign]. Clinvar id is 44354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112216481-A-G is described in Lovd as [Benign]. Variant chr6-112216481-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.196-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.196-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152220 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0189 AC: 4749 AN: 250622 Hom.: 61 AF XY: 0.0200 AC XY: 2707 AN XY: 135442

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.0205

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0201 AC: 28231 AN: 1401068 Hom.: 362 Cov.: 24 AF XY: 0.0204 AC XY: 14275 AN XY: 701038

Gnomad4 AFR exome AF: 0.00573

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0319

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0212

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0164 AC: 2505 AN: 152338 Hom.: 27 Cov.: 33 AF XY: 0.0167 AC XY: 1243 AN XY: 74488

Gnomad4 AFR AF: 0.00529

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0230 Hom.: 18

Bravo AF: 0.0155

Asia WGS AF: 0.0160 AC: 54 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Mar 10, 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	Feb 16, 2012	196-12T>C in intron 2 of LAMA4: This variant is not expected to have clinical si gnificance because it has been identified in 2% (143/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs78871662). -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1JJ Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0091
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: 48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78871662; hg19: chr6-112537682;