rs1057520165

Variant names:

• chr9-131009252-T-TGGCACCGCG
• rs1057520165
• NM_006059.4:c.42_50dupACCGCGGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4 BP6

The NM_006059.4(LAMC3):​c.42_50dupACCGCGGGC​(p.Ala17_Ala18insProArgAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,293,078 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: LAMC3 NM_006059.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.29
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006059.4.
• BP6: Variant 9-131009252-T-TGGCACCGCG is Benign according to our data. Variant chr9-131009252-T-TGGCACCGCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377211.

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.42_50dupACCGCGGGC	p.Ala17_Ala18insProArgAla	disruptive_inframe_insertion	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.42_50dupACCGCGGGC	p.Ala17_Ala18insProArgAla	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.42_50dupACCGCGGGC	p.Ala17_Ala18insProArgAla	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.42_50dupACCGCGGGC	p.Ala17_Ala18insProArgAla	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 236 AN: 151236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.00 AC: 0 AN: 8078 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 148 AN: 1141734 Hom.: 1 Cov.: 29 AF XY: 0.000118 AC XY: 65 AN XY: 550962

African (AFR) AF: 0.00578 AC: 131 AN: 22670

American (AMR) AF: 0.000222 AC: 2 AN: 8996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14786

East Asian (EAS) AF: 0.00 AC: 0 AN: 24438

South Asian (SAS) AF: 0.00 AC: 0 AN: 38540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957900

Other (OTH) AF: 0.000328 AC: 15 AN: 45786

GnomAD4 genome AF: 0.00157 AC: 238 AN: 151344 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 116 AN XY: 73934

African (AFR) AF: 0.00523 AC: 217 AN: 41468

American (AMR) AF: 0.00118 AC: 18 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67702

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00149 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Occipital pachygyria and polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1057520165; hg19: chr9-133884639;