ENST00000453937.2:c.200A>C

Variant names:

• chr6-112253951-T-G
• rs781999461
• ENST00000453937.2:c.200A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The ENST00000453937.2(LAMA4):​c.200A>C​(p.Gln67Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: LAMA4 ENST00000453937.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.60
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04215452).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453937.2. 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+5A>C		splice_region intron	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105208.3		c.200A>C	p.Gln67Pro	missense	Exon 2 of 2	NP_001098678.1	Q16363-3
	LAMA4	NM_001105209.3		c.200A>C	p.Gln67Pro	missense	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.200A>C	p.Gln67Pro	missense	Exon 2 of 2	ENSP00000398226.2	Q16363-3
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.195+5A>C		splice_region intron	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.195+5A>C		splice_region intron	N/A	ENSP00000374114.4	A0A0A0MTC7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448574 Hom.: 0 Cov.: 31 AF XY: 0.00000695 AC XY: 5 AN XY: 719480

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 42126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39010

South Asian (SAS) AF: 0.0000588 AC: 5 AN: 84974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105180

Other (OTH) AF: 0.00 AC: 0 AN: 59856

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1JJ (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.013
DANN	Benign	0.87
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.6
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.034
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.027	D
Polyphen		0.0090	B
Vest4		0.23
MutPred		0.20		Loss of helix (P = 0.028)
MVP		0.17
ClinPred		0.063	T
GERP RS		-2.4
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs781999461; hg19: chr6-112575153;