rs73658916

Positions:

• chr9-131057028-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006059.4(LAMC3):​c.2039C>T​(p.Thr680Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,048 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (12 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.90

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=0.0069152415).
• BP6: Variant 9-131057028-C-T is Benign according to our data. Variant chr9-131057028-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 378068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131057028-C-T is described in Lovd as [Benign]. Variant chr9-131057028-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00776 (1182/152308) while in subpopulation AFR AF= 0.0259 (1076/41560). AF 95% confidence interval is 0.0246. There are 18 homozygotes in gnomad4. There are 547 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC3	NM_006059.4	c.2039C>T	p.Thr680Met	missense_variant	12/28	ENST00000361069.9	NP_006050.3
LAMC3	XM_011518121.2	c.2039C>T	p.Thr680Met	missense_variant	12/28		XP_011516423.1
LAMC3	XM_006716921.3	c.2039C>T	p.Thr680Met	missense_variant	12/23		XP_006716984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC3	ENST00000361069.9	c.2039C>T	p.Thr680Met	missense_variant	12/28	2	NM_006059.4	ENSP00000354360.4

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1179 AN: 152190 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00228 AC: 574 AN: 251264 Hom.: 5 AF XY: 0.00183 AC XY: 249 AN XY: 135844

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00152 AC: 2217 AN: 1461740 Hom.: 12 Cov.: 33 AF XY: 0.00136 AC XY: 992 AN XY: 727180

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000942

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00776 AC: 1182 AN: 152308 Hom.: 18 Cov.: 33 AF XY: 0.00734 AC XY: 547 AN XY: 74480

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00207 Hom.: 2

Bravo AF: 0.00904

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00271 AC: 329

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.6
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.043
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.29	B
Vest4		0.20
MVP		0.59
MPC		0.23
ClinPred		0.0055	T
GERP RS		-0.94
Varity_R		0.046
gMVP		0.33

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: rs73658916; hg19: chr9-133932415;