rs12208872

Positions:

• chr6-112108977-A-G

Variant summary

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

The ENST00000230538.12(LAMA4):​c.*460T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 178,152 control chromosomes in the GnomAD database, including 5,574 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 0.25 (4733 hom., cov: 32)
  • Exomes 𝑓: 0.23 (841 hom.)
• Consequence: LAMA4 ENST00000230538.12 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.*460T>C		3_prime_UTR_variant	39/39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.*460T>C		3_prime_UTR_variant	39/39	1	NM_001105206.3	ENSP00000230538	A1
LAMA4	ENST00000389463.9	c.*460T>C		3_prime_UTR_variant	39/39	1		ENSP00000374114	P4
LAMA4	ENST00000522006.5	c.*460T>C		3_prime_UTR_variant	39/39	1		ENSP00000429488	P4

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37873 AN: 152052 Hom.: 4734 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.234 AC: 6074 AN: 25980 Hom.: 841 Cov.: 0 AF XY: 0.223 AC XY: 2933 AN XY: 13128

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.249 AC: 37894 AN: 152172 Hom.: 4733 Cov.: 32 AF XY: 0.244 AC XY: 18161 AN XY: 74400

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.263

Alfa AF: 0.263 Hom.: 1085

Bravo AF: 0.251

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.56

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: rs12208872; hg19: chr6-112430180;