rs12748250

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000356082.9(LAMB3):c.2554A>T(p.Met852Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,870 control chromosomes in the GnomAD database, including 17,942 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1194 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16748 hom. )

Consequence

LAMB3
ENST00000356082.9 missense, splice_region

Scores

Splicing: ADA: 0.06802

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.29

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013975799).

BP6

Variant 1-209622984-T-A is Benign according to our data. Variant chr1-209622984-T-A is described in ClinVar as [Benign]. Clinvar id is 255588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMB3	ENST00000356082.9 linkuse as main transcript	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7 linkuse as main transcript	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	17/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5 linkuse as main transcript	c.2554A>T	p.Met852Leu	missense_variant, splice_region_variant	16/22	1		ENSP00000375778	P1

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17436

AN:

152072

Hom.:

1195

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0555

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.120

GnomAD3 exomes

AF:

0.128

AC:

31787

AN:

248634

Hom.:

2499

AF XY:

0.137

AC XY:

18427

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.0518

Gnomad AMR exome

AF:

0.0743

Gnomad ASJ exome

AF:

0.143

Gnomad EAS exome

AF:

0.000438

Gnomad SAS exome

AF:

0.203

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.146

AC:

213631

AN:

1460680

Hom.:

16748

Cov.:

AF XY:

0.149

AC XY:

107970

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.0513

Gnomad4 AMR exome

AF:

0.0779

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.117

Gnomad4 NFE exome

AF:

0.155

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.115

AC:

17436

AN:

152190

Hom.:

1194

Cov.:

AF XY:

0.113

AC XY:

8435

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0555

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.133

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.142

Hom.:

1255

Bravo

AF:

0.109

TwinsUK

AF:

0.162

AC:

599

ALSPAC

AF:

0.160

AC:

618

ESP6500AA

AF:

0.0536

AC:

236

ESP6500EA

AF:

0.153

AC:

1313

ExAC

AF:

0.132

AC:

16021

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2018	Variant summary: LAMB3 c.2554A>T (p.Met852Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.13 in 275034 control chromosomes in the gnomAD database, including 2706 homozygotes (gnomAD). The observed variant frequency is approximately 135-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa phenotype (0.00093), strongly suggesting that the variant is benign. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Amelogenesis imperfecta type 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Junctional epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.66

.;T;.

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

0.48

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.029

B;B;B

Vest4

0.10

MutPred

0.18

Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);

MPC

0.12

ClinPred

0.010

GERP RS

5.2

Varity_R

0.22

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.068

dbscSNV1_RF

Benign

0.20

SpliceAI score (max)

0.020

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