6-112216411-T-C

Position:

chr6-112216411-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001105206.3(LAMA4):c.254A>G(p.Asn85Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

LAMA4
NM_001105206.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17787698).

BP6

Variant 6-112216411-T-C is Benign according to our data. Variant chr6-112216411-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr6-112216411-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.254A>G	p.Asn85Ser	missense_variant	3/39	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12 linkuse as main transcript	c.254A>G	p.Asn85Ser	missense_variant	3/39	1	NM_001105206.3	ENSP00000230538	A1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251226

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000394

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000839

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1JJ

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 01, 2015

The p.Asn85Ser variant in LAMA4 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/10402 African chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 45301300). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Asn85Ser variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2023

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;T;T;.;T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

T;.;.;T;T;T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.88

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.11

T;T;T;T;D;D;D;D

Sift4G

Uncertain

0.035

D;D;D;D;.;.;D;.

Polyphen

0.99

.;.;.;.;.;.;D;.

Vest4

0.67

MVP

0.92

MPC

0.37

ClinPred

0.15

GERP RS

5.8

gMVP

0.61

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