rs199535979

Variant names:

• chr9-131069664-C-T
• rs199535979
• NM_006059.4:c.2891-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-131069664-C-T
• chr9-131069664-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006059.4(LAMC3):​c.2891-8C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00003818
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.112
• Publications: 1 publications found

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]

LAMC3 Gene-Disease associations (from GenCC):

• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Illumina, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 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 VariationId is 194753.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	NM_006059.4	MANE Select	c.2891-8C>T		splice_region intron	N/A	NP_006050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.2891-8C>T		splice_region intron	N/A	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.2891-8C>T		splice_region intron	N/A	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.2891-8C>T		splice_region intron	N/A	ENSP00000625283.1

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

GnomAD2 exomes AF: 0.00272 AC: 607 AN: 223362 AF XY: 0.00284

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 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

African (AFR) AF: 0.000693 AC: 23 AN: 33182

American (AMR) AF: 0.00191 AC: 82 AN: 42850

Ashkenazi Jewish (ASJ) AF: 0.00315 AC: 81 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39090

South Asian (SAS) AF: 0.00484 AC: 404 AN: 83542

European-Finnish (FIN) AF: 0.000793 AC: 41 AN: 51678

Middle Eastern (MID) AF: 0.00582 AC: 25 AN: 4298

European-Non Finnish (NFE) AF: 0.00530 AC: 5855 AN: 1104710

Other (OTH) AF: 0.00520 AC: 310 AN: 59640

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

African (AFR) AF: 0.00111 AC: 46 AN: 41548

American (AMR) AF: 0.00366 AC: 56 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68004

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00403 Hom.: 0

Bravo AF: 0.00320

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Left ventricular noncompaction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199535979; hg19: chr9-133945051;