NM_006059.4:c.-2C>T

Variant names:

• chr9-131009213-C-T
• rs137883250
• NM_006059.4:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006059.4(LAMC3):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,224,466 control chromosomes in the GnomAD database, including 310 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 0.014 (25 hom., cov: 32)
  • Exomes 𝑓: 0.022 (285 hom.)
• Consequence: LAMC3 NM_006059.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.292
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-131009213-C-T is Benign according to our data. Variant chr9-131009213-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291084.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2145/151572) while in subpopulation NFE AF = 0.0222 (1502/67798). AF 95% confidence interval is 0.0212. There are 25 homozygotes in GnomAd4. There are 1035 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.-2C>T		5_prime_UTR	Exon 1 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.-2C>T		5_prime_UTR	Exon 1 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.-2C>T		5_prime_UTR	Exon 1 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.-2C>T		5_prime_UTR	Exon 1 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2143 AN: 151464 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0197 AC: 10 AN: 508 AF XY: 0.0252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0219 AC: 23537 AN: 1072894 Hom.: 285 Cov.: 29 AF XY: 0.0219 AC XY: 11174 AN XY: 510006

African (AFR) AF: 0.00328 AC: 71 AN: 21614

American (AMR) AF: 0.0111 AC: 80 AN: 7216

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 240 AN: 12750

East Asian (EAS) AF: 0.0000440 AC: 1 AN: 22722

South Asian (SAS) AF: 0.00915 AC: 217 AN: 23704

European-Finnish (FIN) AF: 0.0125 AC: 266 AN: 21358

Middle Eastern (MID) AF: 0.0281 AC: 79 AN: 2816

European-Non Finnish (NFE) AF: 0.0237 AC: 21800 AN: 918502

Other (OTH) AF: 0.0185 AC: 783 AN: 42212

GnomAD4 genome AF: 0.0142 AC: 2145 AN: 151572 Hom.: 25 Cov.: 32 AF XY: 0.0140 AC XY: 1035 AN XY: 74082

African (AFR) AF: 0.00422 AC: 175 AN: 41500

American (AMR) AF: 0.0132 AC: 200 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00931 AC: 45 AN: 4834

European-Finnish (FIN) AF: 0.0131 AC: 135 AN: 10294

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0222 AC: 1502 AN: 67798

Other (OTH) AF: 0.0162 AC: 34 AN: 2102

Alfa AF: 0.00491 Hom.: 2

Bravo AF: 0.0139

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		-0.29
PromoterAI		0.35	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs137883250; hg19: chr9-133884600;