6-112179448-T-G

Variant names:

• chr6-112179448-T-G
• rs1158747
• NM_001105206.3:c.1078-1216A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001105206.3(LAMA4):​c.1078-1216A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 152,104 control chromosomes in the GnomAD database, including 14,769 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14764 hom., cov: 32)
  • Exomes 𝑓: 0.42 (5 hom.)
• Consequence: LAMA4 NM_001105206.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.334

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.1078-1216A>C		intron_variant	Intron 9 of 38	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.1078-1216A>C		intron_variant	Intron 9 of 38	1	NM_001105206.3	ENSP00000230538.7

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64836 AN: 151934 Hom.: 14759 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.496

GnomAD4 exome AF: 0.423 AC: 22 AN: 52 Hom.: 5 Cov.: 0 AF XY: 0.400 AC XY: 16 AN XY: 40

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.474

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.427 AC: 64883 AN: 152052 Hom.: 14764 Cov.: 32 AF XY: 0.427 AC XY: 31763 AN XY: 74302

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.497

Alfa AF: 0.477 Hom.: 18632

Bravo AF: 0.433

Asia WGS AF: 0.548 AC: 1901 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.6
DANN	Benign	0.64

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: rs1158747; hg19: chr6-112500650;