chr9-131067128-C-T

Position:

• chr9-131067128-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.2516C>T​(p.Thr839Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,614,162 control chromosomes in the GnomAD database, including 33 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T839T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.06

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=0.024264872).
• BP6: Variant 9-131067128-C-T is Benign according to our data. Variant chr9-131067128-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-131067128-C-T is described in Lovd as [Benign]. Variant chr9-131067128-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00815 (1242/152300) while in subpopulation AFR AF= 0.0277 (1150/41540). AF 95% confidence interval is 0.0264. There are 18 homozygotes in gnomad4. There are 566 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.2516C>T	p.Thr839Met	missense_variant	14/28	ENST00000361069.9	NP_006050.3
LAMC3	XM_011518121.2	c.2516C>T	p.Thr839Met	missense_variant	14/28		XP_011516423.1
LAMC3	XM_006716921.3	c.2516C>T	p.Thr839Met	missense_variant	14/23		XP_006716984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC3	ENST00000361069.9	c.2516C>T	p.Thr839Met	missense_variant	14/28	2	NM_006059.4	ENSP00000354360.4

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152182 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00237 AC: 596 AN: 251366 Hom.: 6 AF XY: 0.00170 AC XY: 231 AN XY: 135902

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00122 AC: 1786 AN: 1461862 Hom.: 15 Cov.: 32 AF XY: 0.00106 AC XY: 770 AN XY: 727234

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00815 AC: 1242 AN: 152300 Hom.: 18 Cov.: 32 AF XY: 0.00760 AC XY: 566 AN XY: 74494

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00147 Hom.: 3

Bravo AF: 0.00913

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00284 AC: 345

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000545

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:5

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)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely 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:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.056	T
Sift4G	Benign	0.081	T
Polyphen		0.61	P
Vest4		0.27
MVP		0.80
MPC		0.35
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.037
gMVP		0.29

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: rs57816762; hg19: chr9-133942515;