rs140769823

Positions:

chr1-209618013-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000228.3(LAMB3):c.2945A>G(p.Asp982Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,614,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D982D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

LAMB3
NM_000228.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 2.31

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01873517).

BP6

Variant 1-209618013-T-C is Benign according to our data. Variant chr1-209618013-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556000.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr1-209618013-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00111 (169/152260) while in subpopulation NFE AF= 0.00196 (133/68010). AF 95% confidence interval is 0.00168. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.2945A>G	p.Asp982Gly	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.2945A>G	p.Asp982Gly	missense_variant	20/23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 linkuse as main transcript	c.2945A>G	p.Asp982Gly	missense_variant	20/23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 linkuse as main transcript	c.2945A>G	p.Asp982Gly	missense_variant	19/22	1		ENSP00000375778.1	Q13751
LAMB3	ENST00000455193.1 linkuse as main transcript	c.152A>G	p.Asp51Gly	missense_variant	2/4	2		ENSP00000398683.1	X1WI29

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00115

AC:

288

AN:

251476

Hom.:

AF XY:

0.00121

AC XY:

165

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00195

AC:

2846

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1432

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00143

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00228

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152260

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00196

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00119

AC:

145

EpiCase

AF:

0.00164

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LAMB3: BS2 -

Junctional epidermolysis bullosa gravis of Herlitz

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 05, 2018

- -

Junctional epidermolysis bullosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;T;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.77

.;T;.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

N;N;N;D

REVEL

Benign

0.28

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.23

T;T;T;.

Polyphen

0.0

B;B;B;.

Vest4

0.74

MVP

0.54

MPC

0.14

ClinPred

0.013

GERP RS

4.5

Varity_R

0.14

gMVP

0.39

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