rs121912482

chr1-209633070-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000228.3(LAMB3):c.628G>A(p.Glu210Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,605,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LAMB3 NM_000228.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.86

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-209633070-C-T is Pathogenic according to our data. Variant chr1-209633070-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	7/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	7/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	7/23	1		P1
LAMB3	ENST00000391911.5	c.628G>A	p.Glu210Lys	missense_variant, splice_region_variant	6/22	1		P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452958 Hom.: 0 Cov.: 29 AF XY: 0.0000152 AC XY: 11 AN XY: 723548

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: 0.0000154

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jan 05, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 06, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 210 of the LAMB3 protein (p.Glu210Lys). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 7706760, 17476356). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14543). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 9690563). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2023	Published functional studies suggest abnormal splicing as multiple aberrant LAMB3 transcripts were identified in skin cells of a homozygous individual; a blistering phenotype was also seen in homozygous knock-in mice (Pasmooij et al., 2007; Hammersen et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7706760, 9690563, 9501007, 9767254, 8618020, 25350318, 17115047, 32124492, 17476356) -

Junctional epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 01, 2023

Variant summary: LAMB3 c.628G>A (p.Glu210Lys) results in a conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Pasmooji_2007). The variant was absent in 251490 control chromosomes (gnomAD). c.628G>A has been reported in the literature in multiple individuals affected with Junctional Epidermolysis Bullosa (examples: McGrath_1995, and Jonkman_2009) . These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.54	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.92	A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.24	B;B;B
Vest4		0.68
MutPred		0.90		Gain of methylation at E210 (P = 0.0029);Gain of methylation at E210 (P = 0.0029);Gain of methylation at E210 (P = 0.0029);
MVP		0.85
MPC		0.17
ClinPred		0.68	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912482; hg19: chr1-209806415;