rs147118520

Variant names:

• chr6-112253812-A-G
• rs147118520
• ENST00000453937.2:c.339T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001105208.3(LAMA4):​c.339T>C​(p.Leu113Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,196 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.014 (209 hom.)
• Consequence: LAMA4 NM_001105208.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.09
• Publications: 3 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]

ENSG00000281613 (HGNC:):

LAMA4-AS1 (HGNC:40333): (LAMA4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 6-112253812-A-G is Benign according to our data. Variant chr6-112253812-A-G is described in ClinVar as Benign. ClinVar VariationId is 163798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1970/152328) while in subpopulation NFE AF = 0.0173 (1174/68022). AF 95% confidence interval is 0.0164. There are 23 homozygotes in GnomAd4. There are 1066 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1970 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	NM_001105206.3	MANE Select	c.195+144T>C		intron	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105208.3		c.339T>C	p.Leu113Leu	synonymous	Exon 2 of 2	NP_001098678.1	Q16363-3
	LAMA4	NM_001105209.3		c.339T>C	p.Leu113Leu	synonymous	Exon 2 of 2	NP_001098679.1	Q16363-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000453937.2	TSL:1	c.339T>C	p.Leu113Leu	synonymous	Exon 2 of 2	ENSP00000398226.2	Q16363-3
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.195+144T>C		intron	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.195+144T>C		intron	N/A	ENSP00000374114.4	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152210 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0136 AC: 3387 AN: 249920 AF XY: 0.0140

Gnomad AFR exome AF: 0.00232

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0579

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0140 AC: 20522 AN: 1461868 Hom.: 209 Cov.: 31 AF XY: 0.0139 AC XY: 10128 AN XY: 727234

African (AFR) AF: 0.00197 AC: 66 AN: 33480

American (AMR) AF: 0.00259 AC: 116 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00384 AC: 331 AN: 86254

European-Finnish (FIN) AF: 0.0557 AC: 2977 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0146 AC: 16242 AN: 1111996

Other (OTH) AF: 0.0116 AC: 699 AN: 60394

GnomAD4 genome AF: 0.0129 AC: 1970 AN: 152328 Hom.: 23 Cov.: 32 AF XY: 0.0143 AC XY: 1066 AN XY: 74478

African (AFR) AF: 0.00257 AC: 107 AN: 41590

American (AMR) AF: 0.00261 AC: 40 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.0574 AC: 609 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1174 AN: 68022

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0130 Hom.: 14

Bravo AF: 0.00776

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0129

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Dilated cardiomyopathy 1JJ (2)
-	-	1	LAMA4-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs147118520; hg19: chr6-112575014;