rs11757455

chr6-112201651-G-A

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.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,122 control chromosomes in the GnomAD database, including 3,545 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (219 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3326 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.45

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=0.006450653).
• BP6: Variant 6-112201651-G-A is Benign according to our data. Variant chr6-112201651-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112201651-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.460C>T	p.Arg154Trp	missense_variant	5/39	ENST00000230538.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.460C>T	p.Arg154Trp	missense_variant	5/39	1	NM_001105206.3	A1

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6673 AN: 152102 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0863

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0522 AC: 13101 AN: 250976 Hom.: 502 AF XY: 0.0574 AC XY: 7788 AN XY: 135602

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0645

Gnomad OTH exome AF: 0.0542

GnomAD4 exome AF: 0.0624 AC: 91135 AN: 1460902 Hom.: 3326 Cov.: 31 AF XY: 0.0640 AC XY: 46547 AN XY: 726756

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0970

Gnomad4 FIN exome AF: 0.0403

Gnomad4 NFE exome AF: 0.0664

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0438 AC: 6666 AN: 152220 Hom.: 219 Cov.: 33 AF XY: 0.0430 AC XY: 3203 AN XY: 74424

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0860

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0660

Gnomad4 OTH AF: 0.0460

Alfa AF: 0.0607 Hom.: 617

Bravo AF: 0.0409

TwinsUK AF: 0.0766 AC: 284

ALSPAC AF: 0.0695 AC: 268

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0649 AC: 558

ExAC AF: 0.0530 AC: 6440

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0669

EpiControl AF: 0.0684

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Dilated cardiomyopathy 1JJ Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;T;T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;.;.;D;D
MetaRNN	Benign	0.0065	T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Vest4		0.48
MPC		0.58
ClinPred		0.036	T
GERP RS		4.2
gMVP		0.64

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: rs11757455; hg19: chr6-112522852; COSMIC: COSV57898447;