9-131069664-C-T

Position:

• chr9-131069664-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006059.4(LAMC3):​c.2891-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,596,980 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (34 hom.)
• Consequence: LAMC3 NM_006059.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003818
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.112

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-131069664-C-T is Benign according to our data. Variant chr9-131069664-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194753.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr9-131069664-C-T is described in Lovd as [Likely_benign]. Variant chr9-131069664-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00347 (528/152236) while in subpopulation SAS AF= 0.00663 (32/4828). AF 95% confidence interval is 0.00501. There are 0 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC3	NM_006059.4	c.2891-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361069.9	NP_006050.3
LAMC3	XM_006716921.3	c.2891-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_006716984.1
LAMC3	XM_011518121.2	c.2891-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011516423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMC3	ENST00000361069.9	c.2891-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_006059.4	ENSP00000354360	P1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00272 AC: 607 AN: 223362 Hom.: 1 AF XY: 0.00284 AC XY: 344 AN XY: 121092

Gnomad AFR exome AF: 0.000522

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00350

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.000686

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00271

GnomAD4 exome AF: 0.00472 AC: 6821 AN: 1444744 Hom.: 34 Cov.: 32 AF XY: 0.00485 AC XY: 3480 AN XY: 717398

Gnomad4 AFR exome AF: 0.000693

Gnomad4 AMR exome AF: 0.00191

Gnomad4 ASJ exome AF: 0.00315

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00484

Gnomad4 FIN exome AF: 0.000793

Gnomad4 NFE exome AF: 0.00530

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.00347 AC: 528 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00339 AC XY: 252 AN XY: 74430

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00403 Hom.: 0

Bravo AF: 0.00320

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LAMC3: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 06, 2020	- -
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
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs199535979; hg19: chr9-133945051;