chr6-112253825-G-C

Position:

chr6-112253825-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000453937.2(LAMA4):c.326C>G(p.Ser109Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,208 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 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

LAMA4
ENST00000453937.2 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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:

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

LAMA4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 6-112253825-G-C is Benign according to our data. Variant chr6-112253825-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43955.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr6-112253825-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA4	NM_001105206.3 linkuse as main transcript	c.195+131C>G		intron_variant		ENST00000230538.12	NP_001098676.2
LAMA4-AS1	NR_121193.1 linkuse as main transcript	n.181+16909G>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.195+131C>G		intron_variant		1	NM_001105206.3	ENSP00000230538	A1
LAMA4-AS1	ENST00000433684.6 linkuse as main transcript	n.684+16909G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

296

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00678

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000468

AC:

117

AN:

250042

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00677

Gnomad AMR exome

AF:

0.000347

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:

0.000153

AC:

223

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00553

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152346

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00683

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.00211

ESP6500AA

AF:

0.00565

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000569

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2012

Variant classified as Uncertain Significance - Favor Benign. The Ser109X variant (LAMA4) has been identified in 0.5% (18/3570) of African American chromosomes b y the NHLBI Exome Sequencing Project in a broad population (http://evs.gs.washin gton.edu/EVS; dbSNP rs138579810). This variant creates a premature stop at codon 109, which is located in the only coding exon in this transcript (NM_001105209) and that is 11 amino acids upstream of the wild-type stop codon. At this positi on, this variant is expected to lead to a truncated protein. However, there is l imited information about the location and level of expression of this transcript . In addition, this variant occurs in the intronic region of transcripts that en code the full LAMA4 protein. Although this data suggests that the Ser109X varian t may be benign, additional information is needed to fully assess its clinical s ignificance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.95

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.16

MutationTaster

Benign

1.0

D;D;N;N;N;N;N

Vest4

0.46

GERP RS

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.50

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.50

Position offset: 3

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