rs141724499

Positions:

• chr9-131085585-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006059.4(LAMC3):​c.4092C>T​(p.Ser1364Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,614,078 control chromosomes in the GnomAD database, including 40 homozygotes. 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 0.0037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (39 hom.)
• Consequence: LAMC3 NM_006059.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.50

Genes affected

LAMC3 (HGNC:6494): (laminin subunit gamma 3) 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 gamma chain isoform laminin, gamma 3. The gamma 3 chain is most similar to the gamma 1 chain, and contains all the 6 domains expected of the gamma chain. It is a component of laminin 12. The gamma 3 chain is broadly expressed in skin, heart, lung, and the reproductive tracts. In skin, it is seen within the basement membrane of the dermal-epidermal junction at points of nerve penetration. Gamma 3 is also a prominent element of the apical surface of ciliated epithelial cells of lung, oviduct, epididymis, ductus deferens, and seminiferous tubules. The distribution of gamma 3-containing laminins along ciliated epithelial surfaces suggests that the apical laminins are important in the morphogenesis and structural stability of the ciliated processes of these cells. [provided by RefSeq, Aug 2011]

LAMC3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-131085585-C-T is Benign according to our data. Variant chr9-131085585-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr9-131085585-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0037 (563/152284) while in subpopulation SAS AF= 0.00704 (34/4830). AF 95% confidence interval is 0.0054. There are 1 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC3	NM_006059.4	c.4092C>T	p.Ser1364Ser	synonymous_variant	25/28	ENST00000361069.9	NP_006050.3
LAMC3	XM_011518121.2	c.4110C>T	p.Ser1370Ser	synonymous_variant	25/28		XP_011516423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC3	ENST00000361069.9	c.4092C>T	p.Ser1364Ser	synonymous_variant	25/28	2	NM_006059.4	ENSP00000354360.4
LAMC3	ENST00000355452.5	c.158-23C>T		intron_variant		1		ENSP00000347627.5
LAMC3	ENST00000678758.1	c.252C>T	p.Ser84Ser	synonymous_variant	3/6			ENSP00000503612.1
LAMC3	ENST00000678544.1	n.1665C>T		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152166 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00589

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00360 AC: 905 AN: 251268 Hom.: 2 AF XY: 0.00386 AC XY: 524 AN XY: 135870

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00496

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00560 AC: 8187 AN: 1461794 Hom.: 39 Cov.: 32 AF XY: 0.00568 AC XY: 4130 AN XY: 727200

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.000750

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152284 Hom.: 1 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74456

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00588

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00511 Hom.: 0

Bravo AF: 0.00341

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00682

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely 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	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	LAMC3: BP4, BP7, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 15, 2015

- -

LAMC3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.4
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs141724499; hg19: chr9-133960972; COSMIC: COSV62654130; COSMIC: COSV62654130;