9-131009306-G-T

Position:

• chr9-131009306-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006059.4(LAMC3):​c.92G>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,443,812 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (58 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.471

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019689202).
• BP6: Variant 9-131009306-G-T is Benign according to our data. Variant chr9-131009306-G-T is described in ClinVar as [Benign]. Clinvar id is 129475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.92G>T	p.Arg31Leu	missense_variant	1/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.92G>T	p.Arg31Leu	missense_variant	1/28
LAMC3	XM_006716921.3	c.92G>T	p.Arg31Leu	missense_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.92G>T	p.Arg31Leu	missense_variant	1/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2867 AN: 151734 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00558

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.0111

GnomAD3 exomes AF: 0.00147 AC: 90 AN: 61058 Hom.: 2 AF XY: 0.00131 AC XY: 47 AN XY: 35756

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.000542

Gnomad SAS exome AF: 0.000160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000585

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00194 AC: 2502 AN: 1291970 Hom.: 58 Cov.: 30 AF XY: 0.00168 AC XY: 1065 AN XY: 635432

Gnomad4 AFR exome AF: 0.0682

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.000140

Gnomad4 EAS exome AF: 0.000361

Gnomad4 SAS exome AF: 0.000264

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.0190 AC: 2887 AN: 151842 Hom.: 105 Cov.: 32 AF XY: 0.0183 AC XY: 1355 AN XY: 74224

Gnomad4 AFR AF: 0.0659

Gnomad4 AMR AF: 0.00557

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000383

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0102 Hom.: 5

Bravo AF: 0.0213

ESP6500AA AF: 0.0370 AC: 58

ESP6500EA AF: 0.00146 AC: 5

ExAC AF: 0.00156 AC: 64

Asia WGS AF: 0.00698 AC: 24 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.080
Sift	Uncertain	0.021	D
Sift4G	Benign	0.098	T
Polyphen		0.61	P
Vest4		0.090
MVP		0.60
MPC		0.23
ClinPred		0.011	T
GERP RS		1.2
Varity_R		0.17
gMVP		0.57

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: rs116259120; hg19: chr9-133884693;