6-112253988-C-T

Variant names:

• chr6-112253988-C-T
• NM_001105206.3:c.163G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105206.3(LAMA4):​c.163G>A​(p.Val55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V55L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.163G>A	p.Val55Met	missense_variant	Exon 2 of 39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.163G>A	p.Val55Met	missense_variant	Exon 2 of 39	1	NM_001105206.3	ENSP00000230538.7
ENSG00000281613	ENST00000587816.2	c.-398+17072C>T		intron_variant	Intron 1 of 4	5		ENSP00000487146.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433310 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 29, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;.;T;.;.;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.80	T;.;.;T;T;T;T;T;T;.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;.;.;.;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.50	N;N;N;N;N;N;N;N;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;.;.;D;.;.;D;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;D;D;D
Vest4		0.35
MutPred		0.71		Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);Gain of glycosylation at P53 (P = 0.1018);
MVP		0.28
MPC		0.13
ClinPred		1.0	D
GERP RS		2.5
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-112575190;