6-112136188-C-T

Position:

• chr6-112136188-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001105206.3(LAMA4):​c.3349G>A​(p.Gly1117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,611,098 control chromosomes in the GnomAD database, including 440,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (45980 hom., cov: 32)
  • Exomes 𝑓: 0.73 (394636 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.50

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]

LOC107986633 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.803636E-7).
• BP6: Variant 6-112136188-C-T is Benign according to our data. Variant chr6-112136188-C-T is described in ClinVar as [Benign]. Clinvar id is 44376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112136188-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.3349G>A	p.Gly1117Ser	missense_variant	25/39	ENST00000230538.12
LOC107986633	XR_001744299.2	n.440-19132C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.3349G>A	p.Gly1117Ser	missense_variant	25/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117540 AN: 151994 Hom.: 45922 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.758

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.764

GnomAD3 exomes AF: 0.775 AC: 194311 AN: 250840 Hom.: 76146 AF XY: 0.773 AC XY: 104758 AN XY: 135580

Gnomad AFR exome AF: 0.868

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.854

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.702

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.733 AC: 1069192 AN: 1458986 Hom.: 394636 Cov.: 34 AF XY: 0.736 AC XY: 534390 AN XY: 726006

Gnomad4 AFR exome AF: 0.862

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.758

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.741

Gnomad4 NFE exome AF: 0.708

Gnomad4 OTH exome AF: 0.747

GnomAD4 genome AF: 0.774 AC: 117660 AN: 152112 Hom.: 45980 Cov.: 32 AF XY: 0.777 AC XY: 57746 AN XY: 74346

Gnomad4 AFR AF: 0.860

Gnomad4 AMR AF: 0.812

Gnomad4 ASJ AF: 0.758

Gnomad4 EAS AF: 0.864

Gnomad4 SAS AF: 0.872

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.707

Gnomad4 OTH AF: 0.766

Alfa AF: 0.724 Hom.: 77870

Bravo AF: 0.778

ESP6500AA AF: 0.858 AC: 3782

ESP6500EA AF: 0.697 AC: 5990

ExAC AF: 0.769 AC: 93360

Asia WGS AF: 0.890 AC: 3092 AN: 3478

EpiCase AF: 0.705

EpiControl AF: 0.709

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1JJ Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.19
DEOGEN2	Benign	0.0051	T;T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.019	T;.;.;T
MetaRNN	Benign	9.8e-7	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.4	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.53	T;T;T;T
Vest4		0.039
MPC		0.12
ClinPred		0.0088	T
GERP RS		5.9
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2032567; hg19: chr6-112457390; COSMIC: COSV57893884;