18-23689699-CG-C

Variant names:

• chr18-23689699-CG-C
• rs1555670401
• NM_198129.4:c.18delG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_198129.4(LAMA3):​c.18delG​(p.Pro7LeufsTer151) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAMA3 NM_198129.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.98
• Publications: 0 publications found

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

LAMA3 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• laryngo-onycho-cutaneous syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 170 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198129.4. 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
	LAMA3	NM_198129.4	MANE Select	c.18delG	p.Pro7LeufsTer151	frameshift	Exon 1 of 75	NP_937762.2	Q16787-2
	LAMA3	NM_001127717.4		c.18delG	p.Pro7LeufsTer151	frameshift	Exon 1 of 74	NP_001121189.2	A0A0A0MSA0
	LAMA3	NM_001302996.2		c.18delG	p.Pro7LeufsTer151	frameshift	Exon 1 of 9	NP_001289925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.18delG	p.Pro7LeufsTer151	frameshift	Exon 1 of 75	ENSP00000324532.8	Q16787-2
	LAMA3	ENST00000399516.7	TSL:1	c.18delG	p.Pro7LeufsTer151	frameshift	Exon 1 of 74	ENSP00000382432.2	Q16787-3
	LAMA3	ENST00000585600.5	TSL:1	n.18delG		non_coding_transcript_exon	Exon 1 of 13	ENSP00000468316.1	A0A075B783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1169778 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 562390

African (AFR) AF: 0.00 AC: 0 AN: 23306

American (AMR) AF: 0.00 AC: 0 AN: 8836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15990

East Asian (EAS) AF: 0.00 AC: 0 AN: 26902

South Asian (SAS) AF: 0.00 AC: 0 AN: 41102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974248

Other (OTH) AF: 0.00 AC: 0 AN: 47878

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Junctional epidermolysis bullosa gravis of Herlitz (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

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: rs1555670401; hg19: chr18-21269663;