rs121912486

Positions:

• chr1-209633102-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000228.3(LAMB3):​c.596G>C​(p.Gly199Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.354

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20117939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.596G>C	p.Gly199Ala	missense_variant	7/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.596G>C	p.Gly199Ala	missense_variant	7/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.596G>C	p.Gly199Ala	missense_variant	7/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.596G>C	p.Gly199Ala	missense_variant	6/22	1		ENSP00000375778	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460532 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726724

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2007

- -

Junctional epidermolysis bullosa gravis of Herlitz Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.67	.;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.014	B;B;B
Vest4		0.19
MutPred		0.83		Loss of catalytic residue at Q204 (P = 0.1256);Loss of catalytic residue at Q204 (P = 0.1256);Loss of catalytic residue at Q204 (P = 0.1256);
MVP		0.73
MPC		0.13
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.066
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121912486; hg19: chr1-209806447;