rs140540789

chr9-131067129-G-Achr9-131067129-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_006059.4(LAMC3):c.2517G>A(p.Thr839=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,134 control chromosomes in the GnomAD database, including 8 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 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (7 hom.)
• Consequence: LAMC3 NM_006059.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -6.23

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-131067129-G-A is Benign according to our data. Variant chr9-131067129-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378069.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr9-131067129-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (428/152276) while in subpopulation NFE AF= 0.00401 (273/68014). AF 95% confidence interval is 0.00362. There are 1 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.2517G>A	p.Thr839=	synonymous_variant	14/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.2517G>A	p.Thr839=	synonymous_variant	14/28
LAMC3	XM_006716921.3	c.2517G>A	p.Thr839=	synonymous_variant	14/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.2517G>A	p.Thr839=	synonymous_variant	14/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00246 AC: 618 AN: 251364 Hom.: 1 AF XY: 0.00260 AC XY: 354 AN XY: 135898

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00386 AC: 5641 AN: 1461858 Hom.: 7 Cov.: 32 AF XY: 0.00375 AC XY: 2725 AN XY: 727236

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.00454

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74462

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00264

EpiCase AF: 0.00371

EpiControl AF: 0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LAMC3: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2015	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	Genetic Services Laboratory, University of Chicago	Oct 05, 2016	- -

LAMC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 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	0.17
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140540789; hg19: chr9-133942516;