rs2229467

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000228.3(LAMB3):c.2962C>T(p.Arg988Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00093 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R988Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 1 hom. )

Consequence

LAMB3
NM_000228.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.46

Variant links:

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]

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025251806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.2962C>T	p.Arg988Trp	missense_variant	20/23	ENST00000356082.9	NP_000219.2	Q13751A0A0S2Z3R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMB3	ENST00000356082.9 linkuse as main transcript	c.2962C>T	p.Arg988Trp	missense_variant	20/23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 linkuse as main transcript	c.2962C>T	p.Arg988Trp	missense_variant	20/23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 linkuse as main transcript	c.2962C>T	p.Arg988Trp	missense_variant	19/22	1		ENSP00000375778.1	Q13751
LAMB3	ENST00000455193.1 linkuse as main transcript	c.169C>T	p.Arg57Trp	missense_variant	2/4	2		ENSP00000398683.1	X1WI29

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000887

AC:

223

AN:

251470

Hom.:

AF XY:

0.000883

AC XY:

120

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000960

AC:

1403

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000950

AC XY:

691

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000644

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000863

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000980

AC:

119

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Junctional epidermolysis bullosa gravis of Herlitz

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2016	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 988 of the LAMB3 protein (p.Arg988Trp). This variant is present in population databases (rs2229467, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with LAMB3-related conditions (PMID: 25950805). ClinVar contains an entry for this variant (Variation ID: 550265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LAMB3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 31, 2024

Variant summary: LAMB3 c.2962C>T (p.Arg988Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 1614128 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa (0.00093 vs 0.0024), allowing no conclusion about variant significance. c.2962C>T has been reported in the literature in individuals affected with Junctional Epidermolysis Bullosa as a compound heterozygous genotype without reported phase and heterozygous phenotype in the presence of variants in an alternate gene associated with the phenotype (e.g. Saraiya_2015, Lucky_2018, Vahidnezhad_2018). These reports do not provide unequivocal conclusions about association of the variant with Junctional Epidermolysis Bullosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 550265). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Junctional epidermolysis bullosa gravis of Herlitz;C0268374:Junctional epidermolysis bullosa, non-Herlitz type;C4011403:Amelogenesis imperfecta type 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Junctional epidermolysis bullosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.061

LIST_S2

Uncertain

0.89

.;D;.;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;.

Polyphen

0.98

D;D;D;.

Vest4

0.80

MVP

0.58

MPC

0.39

ClinPred

0.038

GERP RS

1.9

Varity_R

0.10

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over