6-112254011-G-A

Position:

• chr6-112254011-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001105206.3(LAMA4):​c.140C>T​(p.Pro47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P47P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.675

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

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057860762).
• BP6: Variant 6-112254011-G-A is Benign according to our data. Variant chr6-112254011-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.140C>T	p.Pro47Leu	missense_variant	2/39	ENST00000230538.12	NP_001098676.2
LAMA4-AS1	NR_121193.1	n.181+17095G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.140C>T	p.Pro47Leu	missense_variant	2/39	1	NM_001105206.3	ENSP00000230538	A1
LAMA4-AS1	ENST00000433684.6	n.684+17095G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2019

The p.P47L variant (also known as c.140C>T), located in coding exon 1 of the LAMA4 gene, results from a C to T substitution at nucleotide position 140. The proline at codon 47 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 13, 2016

p.Pro47Leu in exon 2 of LAMA4: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, multiple mammals (bat, shrew, elephant shrew, armadillo, and Tasmanian devil ) have a leucine (Leu) at this position despite high nearby amino acid conservat ion. In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not sug gest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;T;T;.;T;.;.;T;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.78	T;.;.;T;T;T;T;T;T;.;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.058	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;.;.;.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.67	N;N;N;N;N;N;N;D;D;D;D;D
REVEL	Benign	0.073
Sift	Benign	0.054	T;T;T;T;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;.;.;D;.;.;D;D;.
Polyphen		0.026	.;.;.;.;.;.;B;.;.;B;B;B
Vest4		0.14
MutPred		0.30		Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);Loss of glycosylation at P47 (P = 0.0403);
MVP		0.35
MPC		0.12
ClinPred		0.17	T
GERP RS		1.1
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs727503115; hg19: chr6-112575213;