NM_198129.4:c.394delC

Variant names:

• chr18-23714015-TC-T
• rs887748208
• NM_198129.4:c.394delC

Variant summary

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

The NM_198129.4(LAMA3):​c.394delC​(p.Leu132CysfsTer26) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000161 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: LAMA3 NM_198129.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.97
• 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

ENSG00000306094 (HGNC:):

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.394delC	p.Leu132CysfsTer26	frameshift	Exon 2 of 75	NP_937762.2	Q16787-2
	LAMA3	NM_001127717.4		c.394delC	p.Leu132CysfsTer26	frameshift	Exon 2 of 74	NP_001121189.2	A0A0A0MSA0
	LAMA3	NM_001302996.2		c.394delC	p.Leu132CysfsTer26	frameshift	Exon 2 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.394delC	p.Leu132CysfsTer26	frameshift	Exon 2 of 75	ENSP00000324532.8	Q16787-2
	LAMA3	ENST00000399516.7	TSL:1	c.394delC	p.Leu132CysfsTer26	frameshift	Exon 2 of 74	ENSP00000382432.2	Q16787-3
	LAMA3	ENST00000585600.5	TSL:1	n.394delC		non_coding_transcript_exon	Exon 2 of 13	ENSP00000468316.1	A0A075B783

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151902 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249534 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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461818 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151902 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74190

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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		5.0
Mutation Taster		=3/197	disease causing (fs/PTC)

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: rs887748208; hg19: chr18-21293979;