rs12208872

Variant names:

• chr6-112108977-A-G
• rs12208872
• NM_001105206.3:c.*460T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001105206.3(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 NM_001105206.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573
• Publications: 6 publications found

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]

LAMA4 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1JJ

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.*460T>C		3_prime_UTR_variant	Exon 39 of 39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.*460T>C		3_prime_UTR_variant	Exon 39 of 39	1	NM_001105206.3	ENSP00000230538.7

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

African (AFR) AF: 0.233 AC: 95 AN: 408

American (AMR) AF: 0.196 AC: 567 AN: 2890

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 127 AN: 492

East Asian (EAS) AF: 0.315 AC: 499 AN: 1584

South Asian (SAS) AF: 0.129 AC: 385 AN: 2992

European-Finnish (FIN) AF: 0.216 AC: 203 AN: 938

Middle Eastern (MID) AF: 0.250 AC: 19 AN: 76

European-Non Finnish (NFE) AF: 0.254 AC: 3851 AN: 15148

Other (OTH) AF: 0.226 AC: 328 AN: 1452

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

African (AFR) AF: 0.238 AC: 9897 AN: 41524

American (AMR) AF: 0.206 AC: 3155 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1679 AN: 5188

South Asian (SAS) AF: 0.157 AC: 757 AN: 4816

European-Finnish (FIN) AF: 0.207 AC: 2186 AN: 10584

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18340 AN: 67984

Other (OTH) AF: 0.263 AC: 555 AN: 2112

Alfa AF: 0.263 Hom.: 1854

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
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12208872; hg19: chr6-112430180;