rs138579810

Variant names:

• chr6-112253825-G-C
• rs138579810
• ENST00000453937.2:c.326C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001105208.3(LAMA4):​c.326C>G​(p.Ser109*) 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 NM_001105208.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.15

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

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 rank	MANE	Protein	UniProt
LAMA4	NM_001105206.3	c.195+131C>G		intron_variant	Intron 2 of 38	ENST00000230538.12	NP_001098676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA4	ENST00000230538.12	c.195+131C>G		intron_variant	Intron 2 of 38	1	NM_001105206.3	ENSP00000230538.7
ENSG00000281613	ENST00000587816.2	c.-398+16909G>C		intron_variant	Intron 1 of 4	5		ENSP00000487146.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152228 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135634

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.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 727226

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.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74504

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.: 0

Bravo AF: 0.00211

ESP6500AA AF: 0.00565 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000569 AC: 69

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jan 13, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.16	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

Other links and lift over

dbSNP: rs138579810; hg19: chr6-112575027;