rs117621658

Positions:

• chr9-131069872-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006059.4(LAMC3):​c.3069+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,565,466 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (10 hom.)
• Consequence: LAMC3 NM_006059.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-131069872-C-T is Benign according to our data. Variant chr9-131069872-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435731.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (453/152344) while in subpopulation NFE AF= 0.00484 (329/68036). AF 95% confidence interval is 0.0044. There are 0 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.3069+22C>T		intron_variant		ENST00000361069.9
LAMC3	XM_006716921.3	c.3069+22C>T		intron_variant
LAMC3	XM_011518121.2	c.3069+22C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.3069+22C>T		intron_variant		2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00296 AC: 524 AN: 177020 Hom.: 3 AF XY: 0.00299 AC XY: 283 AN XY: 94546

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00898

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00235

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00409 AC: 5777 AN: 1413122 Hom.: 10 Cov.: 31 AF XY: 0.00401 AC XY: 2802 AN XY: 698794

Gnomad4 AFR exome AF: 0.000523

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00981

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00459

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.00273 AC XY: 203 AN XY: 74494

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00426 Hom.: 0

Bravo AF: 0.00267

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 19, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.73

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: rs117621658; hg19: chr9-133945259;