9-131072662-A-G

Position:

• chr9-131072662-A-G

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.3244A>G​(p.Ser1082Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 1,610,304 control chromosomes in the GnomAD database, including 535,209 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44804 hom., cov: 31)
  • Exomes 𝑓: 0.82 (490405 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.511

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=8.411099E-7).
• BP6: Variant 9-131072662-A-G is Benign according to our data. Variant chr9-131072662-A-G is described in ClinVar as [Benign]. Clinvar id is 129460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131072662-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.3244A>G	p.Ser1082Gly	missense_variant	19/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.3244A>G	p.Ser1082Gly	missense_variant	19/28
LAMC3	XM_006716921.3	c.3244A>G	p.Ser1082Gly	missense_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.3244A>G	p.Ser1082Gly	missense_variant	19/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115299 AN: 151892 Hom.: 44801 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.788

GnomAD3 exomes AF: 0.789 AC: 193825 AN: 245808 Hom.: 77625 AF XY: 0.799 AC XY: 106577 AN XY: 133328

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.647

Gnomad SAS exome AF: 0.814

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.843

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.818 AC: 1192532 AN: 1458294 Hom.: 490405 Cov.: 55 AF XY: 0.820 AC XY: 594645 AN XY: 725364

Gnomad4 AFR exome AF: 0.599

Gnomad4 AMR exome AF: 0.669

Gnomad4 ASJ exome AF: 0.918

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.812

Gnomad4 FIN exome AF: 0.861

Gnomad4 NFE exome AF: 0.832

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.759 AC: 115336 AN: 152010 Hom.: 44804 Cov.: 31 AF XY: 0.763 AC XY: 56664 AN XY: 74312

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.719

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.867

Gnomad4 NFE AF: 0.840

Gnomad4 OTH AF: 0.788

Alfa AF: 0.822 Hom.: 109672

Bravo AF: 0.740

TwinsUK AF: 0.834 AC: 3092

ALSPAC AF: 0.826 AC: 3182

ESP6500AA AF: 0.624 AC: 2748

ESP6500EA AF: 0.841 AC: 7235

ExAC AF: 0.788 AC: 95696

Asia WGS AF: 0.721 AC: 2507 AN: 3476

EpiCase AF: 0.850

EpiControl AF: 0.841

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Occipital pachygyria and polymicrogyria Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.64
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.016
Sift	Benign	0.52	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.13
ClinPred		0.0012	T
GERP RS		2.2
Varity_R		0.035
gMVP		0.19

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: rs2275140; hg19: chr9-133948049; COSMIC: COSV63088882;