rs35605307

chr6-112141361-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001105206.3(LAMA4):c.2810A>G(p.Glu937Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.52

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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.012752295).
• BP6: Variant 6-112141361-T-C is Benign according to our data. Variant chr6-112141361-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112141361-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 503 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.2810A>G	p.Glu937Gly	missense_variant	21/39	ENST00000230538.12
LOC107986633	XR_001744299.2	n.440-13959T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.2810A>G	p.Glu937Gly	missense_variant	21/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000868 AC: 218 AN: 251190 Hom.: 2 AF XY: 0.000633 AC XY: 86 AN XY: 135756

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000318

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: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000364 AC: 532 AN: 1461800 Hom.: 4 Cov.: 32 AF XY: 0.000297 AC XY: 216 AN XY: 727210

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152270 Hom.: 6 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74454

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000550 Hom.: 1

Bravo AF: 0.00354

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2012	Glu930Gly in exon 21 of LAMA4: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (30/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35605307). Glu930Gly in exon 21 of LAMA4 (r s35605307; allele frequency = 0.8%, 30/3738) ** -

Dilated cardiomyopathy 1JJ Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Aug 21, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2015

This alteration is classified as 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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;.;D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.085	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Vest4		0.94
MVP		0.87
MPC		0.49
ClinPred		0.023	T
GERP RS		5.7
gMVP		0.75

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: rs35605307; hg19: chr6-112462563;