chr18-23939322-C-T

Variant names:

• chr18-23939322-C-T
• rs137852758
• NM_198129.4:c.8962C>T

Variant summary

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

The NM_198129.4(LAMA3):​c.8962C>T​(p.Gln2988*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAMA3 NM_198129.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.08
• Publications: 2 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• junctional epidermolysis bullosa Herlitz type

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

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, 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 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.8962C>T	p.Gln2988*	stop_gained	Exon 68 of 75	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.4135C>T	p.Gln1379*	stop_gained	Exon 31 of 38	NP_000218.3
	LAMA3	NM_001127717.4		c.8794C>T	p.Gln2932*	stop_gained	Exon 67 of 74	NP_001121189.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.8962C>T	p.Gln2988*	stop_gained	Exon 68 of 75	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.4135C>T	p.Gln1379*	stop_gained	Exon 31 of 38	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.8794C>T	p.Gln2932*	stop_gained	Exon 67 of 74	ENSP00000382432.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000131 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epidermolysis bullosa, junctional 2A, intermediate (1)
-	1	-	Epidermolysis bullosa, junctional 2B, severe (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.55	D
PhyloP100		1.1
Vest4		0.89
GERP RS		2.6
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs137852758; hg19: chr18-21519286;