rs35349917

Positions:

• chr6-112216385-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.280G>A​(p.Gly94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,612,474 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (74 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (57 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.28

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006398976).
• BP6: Variant 6-112216385-C-T is Benign according to our data. Variant chr6-112216385-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112216385-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.280G>A	p.Gly94Ser	missense_variant	3/39	ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.280G>A	p.Gly94Ser	missense_variant	3/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2424 AN: 152162 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00441 AC: 1108 AN: 251226 Hom.: 26 AF XY: 0.00337 AC XY: 458 AN XY: 135762

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00181 AC: 2640 AN: 1460194 Hom.: 57 Cov.: 30 AF XY: 0.00167 AC XY: 1214 AN XY: 726502

Gnomad4 AFR exome AF: 0.0578

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.0160 AC: 2429 AN: 152280 Hom.: 74 Cov.: 33 AF XY: 0.0157 AC XY: 1168 AN XY: 74466

Gnomad4 AFR AF: 0.0557

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00298 Hom.: 14

Bravo AF: 0.0179

ESP6500AA AF: 0.0576 AC: 254

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00555 AC: 674

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2014	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2012	Benign based on high population frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1JJ Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D;.;.;D;D;D;T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.015	D;D;D;D;T;D;D
Sift4G	Benign	0.43	T;T;T;T;.;.;D
Polyphen		1.0	.;.;.;.;.;.;D
Vest4		0.51
MVP		0.95
MPC		0.36
ClinPred		0.043	T
GERP RS		5.8
gMVP		0.53

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

Other links and lift over

dbSNP: rs35349917; hg19: chr6-112537586; COSMIC: COSV54570458; COSMIC: COSV54570458;