6-112142172-G-C

Position:

chr6-112142172-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001105206.3(LAMA4):c.2614C>G(p.Pro872Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. P872P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.670

Variant links:

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 links:

LOC107986633 (HGNC:):

LOC107986633 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006638229).

BP6

Variant 6-112142172-G-C is Benign according to our data. Variant chr6-112142172-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.2614C>G	p.Pro872Ala	missense_variant	20/39	ENST00000230538.12	NP_001098676.2
LOC107986633	XR_001744299.2 linkuse as main transcript	n.440-13148G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.2614C>G	p.Pro872Ala	missense_variant	20/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

101

AN:

251380

Hom.:

AF XY:

0.000427

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000150

AC:

220

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

727240

show subpopulations

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:

0.00215

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000269

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000486

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 15, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2020

The p.P865A variant (also known as c.2593C>G), located in coding exon 19 of the LAMA4 gene, results from a C to G substitution at nucleotide position 2593. The proline at codon 865 is replaced by alanine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and alanine 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. -

Dilated cardiomyopathy 1JJ

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.033

T;T;T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.61

T;.;.;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.0066

T;T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.035

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.39

T;T;T;T

Vest4

0.26

MVP

0.17

MPC

0.12

ClinPred

0.031

GERP RS

1.2

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over