chr1-209629890-AG-A

Position:

• chr1-209629890-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000228.3(LAMB3):​c.978delC​(p.Phe327fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H326H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: LAMB3 NM_000228.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.76

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 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
• PP5: Variant 1-209629890-AG-A is Pathogenic according to our data. Variant chr1-209629890-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 295120.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.978delC	p.Phe327fs	frameshift_variant	10/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.978delC	p.Phe327fs	frameshift_variant	10/23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.978delC	p.Phe327fs	frameshift_variant	10/23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.978delC	p.Phe327fs	frameshift_variant	9/22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135908

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

This sequence change creates a premature translational stop signal (p.Phe327Leufs*69) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). This variant is present in population databases (rs763559509, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive junctional epidermolysis bullosa (PMID: 11023379). ClinVar contains an entry for this variant (Variation ID: 295120). For these reasons, this variant has been classified as Pathogenic. -

Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 14, 2016

- -

Junctional epidermolysis bullosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The LAMB3 c.978delC (p.Phe327LeufsTer69) variant results in a frameshift and is predicted to result in a premature termination of the protein. The p.Phe327LeufsTer69 variant has been reported in one study in which it is found in a compound heterozygous state with a second null variant in one individual with the severe Herlitz form of junctional epidermolysis bullosa (Nakano et al. 2000). Control data are unavailable for this variant which is reported at a frequency of 0.000309 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of frameshift variants and the supporting evidence, the p.Phe327LeufsTer69 variant is classified as a variant of unknown significance but suspicious for pathogenicity for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs763559509; hg19: chr1-209803235;