1-209618584-G-T

Position:

chr1-209618584-G-T

Variant summary

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

The NM_000228.3(LAMB3):c.2777C>A(p.Ala926Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,230 control chromosomes in the GnomAD database, including 2,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 294 hom., cov: 34)

Exomes 𝑓: 0.038 ( 2678 hom. )

Consequence

LAMB3
NM_000228.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.32

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=0.0017795265).

BP6

Variant 1-209618584-G-T is Benign according to our data. Variant chr1-209618584-G-T is described in ClinVar as [Benign]. Clinvar id is 255591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 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.2777C>A	p.Ala926Asp	missense_variant	19/23	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.2777C>A	p.Ala926Asp	missense_variant	19/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7 linkuse as main transcript	c.2777C>A	p.Ala926Asp	missense_variant	19/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5 linkuse as main transcript	c.2777C>A	p.Ala926Asp	missense_variant	18/22	1		ENSP00000375778	P1
LAMB3	ENST00000455193.1 linkuse as main transcript	c.-17C>A		5_prime_UTR_variant	1/4	2		ENSP00000398683

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4954

AN:

152238

Hom.:

293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00878

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0530

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.274

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0239

Gnomad OTH

AF:

0.0344

GnomAD3 exomes

AF:

0.0593

AC:

14906

AN:

251360

Hom.:

1119

AF XY:

0.0591

AC XY:

8035

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00911

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.272

Gnomad SAS exome

AF:

0.0965

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0433

GnomAD4 exome

AF:

0.0378

AC:

55262

AN:

1461874

Hom.:

2678

Cov.:

AF XY:

0.0394

AC XY:

28683

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00708

Gnomad4 AMR exome

AF:

0.0955

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.263

Gnomad4 SAS exome

AF:

0.0985

Gnomad4 FIN exome

AF:

0.0145

Gnomad4 NFE exome

AF:

0.0249

Gnomad4 OTH exome

AF:

0.0469

GnomAD4 genome

AF:

0.0325

AC:

4949

AN:

152356

Hom.:

294

Cov.:

AF XY:

0.0341

AC XY:

2541

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00880

Gnomad4 AMR

AF:

0.0528

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.273

Gnomad4 SAS

AF:

0.102

Gnomad4 FIN

AF:

0.0104

Gnomad4 NFE

AF:

0.0238

Gnomad4 OTH

AF:

0.0354

Alfa

AF:

0.0289

Hom.:

339

Bravo

AF:

0.0357

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0285

AC:

110

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.0224

AC:

193

ExAC

AF:

0.0558

AC:

6781

Asia WGS

AF:

0.145

AC:

507

AN:

3478

EpiCase

AF:

0.0254

EpiControl

AF:

0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

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

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

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

T;T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

.;T;.

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

M;M;M

MutationTaster

Benign

0.060

P;P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.24

MPC

0.52

ClinPred

0.040

GERP RS

4.1

Varity_R

0.36

gMVP

0.42

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