rs2275135

chr9-131026469-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_006059.4(LAMC3):c.558C>T(p.Arg186=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,358 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (17 hom.)
• Consequence: LAMC3 NM_006059.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.250

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-131026469-C-T is Benign according to our data. Variant chr9-131026469-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 378065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131026469-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00119 (182/152374) while in subpopulation EAS AF= 0.00482 (25/5188). AF 95% confidence interval is 0.00335. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.558C>T	p.Arg186=	synonymous_variant	2/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.558C>T	p.Arg186=	synonymous_variant	2/28
LAMC3	XM_006716921.3	c.558C>T	p.Arg186=	synonymous_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.558C>T	p.Arg186=	synonymous_variant	2/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00164 AC: 410 AN: 249766 Hom.: 1 AF XY: 0.00173 AC XY: 234 AN XY: 135398

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.000974

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00217 AC: 3173 AN: 1460984 Hom.: 17 Cov.: 33 AF XY: 0.00220 AC XY: 1601 AN XY: 726832

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0143

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74520

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00157 Hom.: 1

Bravo AF: 0.00107

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LAMC3: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 27, 2017

- -

Occipital pachygyria and polymicrogyria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.8
Dann	Benign	0.88

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: rs2275135; hg19: chr9-133901856;