rs727503116

Variant names:

• chr6-112254045-T-C
• rs727503116
• NM_001105206.3:c.106A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001105206.3(LAMA4):​c.106A>G​(p.Ile36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,449,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I36T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0380
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07138422).
• BP6: Variant 6-112254045-T-C is Benign according to our data. Variant chr6-112254045-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163800.
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.106A>G	p.Ile36Val	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.106A>G	p.Ile36Val	missense_variant	Exon 2 of 39	1	NM_001105206.3	ENSP00000230538.7
ENSG00000281613	ENST00000587816.2	c.-398+17129T>C		intron_variant	Intron 1 of 4	5		ENSP00000487146.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1449918 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 720064

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 42470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39306

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000217 AC: 24 AN: 1106416

Other (OTH) AF: 0.00 AC: 0 AN: 59990

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Sep 27, 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 does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

May 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I36V variant (also known as c.106A>G), located in coding exon 1 of the LAMA4 gene, results from an A to G substitution at nucleotide position 106. The isoleucine at codon 36 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. 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

May 03, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile36Val variant in exon 2 of LAMA4: This variant is not expected to have clinic al significance due to a lack of conservation across species, including mammals. Of note, kangaroo rat, rabbit, microbat, rock hyrax and platypus have a valine (Val) at this position despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2) do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.0093	T;T;T;T;.;T;.;.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.58	T;.;.;T;T;T;T;T;T;.;.;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.071	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;.;.;.;N;N;N
PhyloP100		0.038
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.010	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;.;.;T;.;.;D;D;.
Polyphen		0.015	.;.;.;.;.;.;B;.;.;B;B;B
Vest4		0.14
MutPred		0.60		Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);Gain of disorder (P = 0.1179);
MVP		0.14
MPC		0.099
ClinPred		0.11	T
GERP RS		-4.8
PromoterAI		0.015	Neutral
gMVP		0.39
Mutation Taster		=84/16	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: rs727503116; hg19: chr6-112575247;