chr18-23939322-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_198129.4(LAMA3):​c.8962C>T​(p.Gln2988Ter) 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

Scores

2
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.08
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LAMA3NM_198129.4 linkuse as main transcriptc.8962C>T p.Gln2988Ter stop_gained 68/75 ENST00000313654.14
LAMA3NM_000227.6 linkuse as main transcriptc.4135C>T p.Gln1379Ter stop_gained 31/38 ENST00000269217.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LAMA3ENST00000313654.14 linkuse as main transcriptc.8962C>T p.Gln2988Ter stop_gained 68/751 NM_198129.4 P1Q16787-2
LAMA3ENST00000269217.11 linkuse as main transcriptc.4135C>T p.Gln1379Ter stop_gained 31/381 NM_000227.6 Q16787-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epidermolysis bullosa, junctional 2A, intermediate Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2002- -
Epidermolysis bullosa, junctional 2B, severe Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.89
GERP RS
2.6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852758; hg19: chr18-21519286; API