rs140540789

Variant names:

• chr9-131067129-G-A
• rs140540789
• NM_006059.4:c.2517G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-131067129-G-A
• chr9-131067129-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_006059.4(LAMC3):​c.2517G>A​(p.Thr839Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,134 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (7 hom.)
• Consequence: LAMC3 NM_006059.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -6.23
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-131067129-G-A is Benign according to our data. Variant chr9-131067129-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378069.
• BP7: Synonymous conserved (PhyloP=-6.23 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.2517G>A	p.Thr839Thr	synonymous	Exon 14 of 28	NP_006050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.2517G>A	p.Thr839Thr	synonymous	Exon 14 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.2517G>A	p.Thr839Thr	synonymous	Exon 14 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.2517G>A	p.Thr839Thr	synonymous	Exon 14 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00246 AC: 618 AN: 251364 AF XY: 0.00260

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00386 AC: 5641 AN: 1461858 Hom.: 7 Cov.: 32 AF XY: 0.00375 AC XY: 2725 AN XY: 727236

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00224 AC: 100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86258

European-Finnish (FIN) AF: 0.00202 AC: 108 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00454 AC: 5047 AN: 1112006

Other (OTH) AF: 0.00280 AC: 169 AN: 60396

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74462

African (AFR) AF: 0.00108 AC: 45 AN: 41562

American (AMR) AF: 0.00359 AC: 55 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00264

EpiCase AF: 0.00371

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	LAMC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.17
DANN	Benign	0.72
PhyloP100		-6.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140540789; hg19: chr9-133942516;