chr6-112253958-C-T

Variant names:

• chr6-112253958-C-T
• rs1787662565
• ENST00000453937.2:c.193G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105206.3(LAMA4):​c.193G>A​(p.Glu65Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E65V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.285
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10932556).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105206.3. 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.193G>A	p.Glu65Lys	missense splice_region	Exon 2 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105208.3		c.193G>A	p.Glu65Lys	missense	Exon 2 of 2	NP_001098678.1	Q16363-3
	LAMA4	NM_001105209.3		c.193G>A	p.Glu65Lys	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.193G>A	p.Glu65Lys	missense	Exon 2 of 2	ENSP00000398226.2	Q16363-3
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.193G>A	p.Glu65Lys	missense splice_region	Exon 2 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.193G>A	p.Glu65Lys	missense splice_region	Exon 2 of 39	ENSP00000374114.4	A0A0A0MTC7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440468 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714804

African (AFR) AF: 0.00 AC: 0 AN: 32956

American (AMR) AF: 0.00 AC: 0 AN: 40538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 38468

South Asian (SAS) AF: 0.00 AC: 0 AN: 84244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101070

Other (OTH) AF: 0.00 AC: 0 AN: 59586

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	7.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.28
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.020
Sift	Benign	0.21	T
Sift4G	Uncertain	0.028	D
Polyphen		0.27	B
Vest4		0.15
MutPred		0.45		Gain of ubiquitination at E65 (P = 0.0325)
MVP		0.57
MPC		0.14
ClinPred		0.14	T
GERP RS		0.89
gMVP		0.71
Mutation Taster		=92/8	polymorphism

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: rs1787662565; hg19: chr6-112575160;