rs971402

Positions:

• chr6-112166698-G-A

Variant summary

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

The NM_001105206.3(LAMA4):​c.1552-1422C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 151,944 control chromosomes in the GnomAD database, including 17,511 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 0.47 (17511 hom., cov: 32)
• Consequence: LAMA4 NM_001105206.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.1552-1422C>T		intron_variant		ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.1552-1422C>T		intron_variant		1	NM_001105206.3	A1
LAMA4	ENST00000389463.9	c.1531-1422C>T		intron_variant		1		P4
LAMA4	ENST00000522006.5	c.1531-1422C>T		intron_variant		1		P4
LAMA4	ENST00000424408.6	c.1531-1422C>T		intron_variant		5		P4

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70895 AN: 151826 Hom.: 17514 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.535

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.467 AC: 70926 AN: 151944 Hom.: 17511 Cov.: 32 AF XY: 0.459 AC XY: 34072 AN XY: 74270

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.354

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.533

Alfa AF: 0.553 Hom.: 42137

Bravo AF: 0.467

Asia WGS AF: 0.393 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.6
DANN	Benign	0.37

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: rs971402; hg19: chr6-112487900; COSMIC: COSV57906997; COSMIC: COSV57906997;