chr1-209618584-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A926G) has been classified 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

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Ambry Genetics
amelogenesis imperfecta type 1A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.2777C>A	p.Ala926Asp	missense_variant	Exon 19 of 23	ENST00000356082.9	NP_000219.2	Q13751A0A0S2Z3R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMB3	ENST00000356082.9 link	c.2777C>A	p.Ala926Asp	missense_variant	Exon 19 of 23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 link	c.2777C>A	p.Ala926Asp	missense_variant	Exon 19 of 23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 link	c.2777C>A	p.Ala926Asp	missense_variant	Exon 18 of 22	1		ENSP00000375778.1	Q13751
LAMB3	ENST00000455193.1 link	c.-17C>A		5_prime_UTR_variant	Exon 1 of 4	2		ENSP00000398683.1	X1WI29

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

GnomAD2 exomes

AF:

0.0593

AC:

14906

AN:

251360

AF XY:

0.0591

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 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

African (AFR)

AF:

0.00708

AC:

237

AN:

33478

American (AMR)

AF:

0.0955

AC:

4269

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

356

AN:

26134

East Asian (EAS)

AF:

0.263

AC:

10453

AN:

39698

South Asian (SAS)

AF:

0.0985

AC:

8492

AN:

86256

European-Finnish (FIN)

AF:

0.0145

AC:

776

AN:

53416

Middle Eastern (MID)

AF:

0.0362

AC:

209

AN:

5768

European-Non Finnish (NFE)

AF:

0.0249

AC:

27640

AN:

1112004

Other (OTH)

AF:

0.0469

AC:

2830

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3543

7087

10630

14174

17717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1290

2580

3870

5160

6450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0325

AC:

4949

AN:

152356

Hom.:

294

Cov.:

AF XY:

0.0341

AC XY:

2541

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00880

AC:

366

AN:

41590

American (AMR)

AF:

0.0528

AC:

809

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.273

AC:

1415

AN:

5176

South Asian (SAS)

AF:

0.102

AC:

493

AN:

4832

European-Finnish (FIN)

AF:

0.0104

AC:

111

AN:

10630

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1622

AN:

68028

Other (OTH)

AF:

0.0354

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

234

469

703

938

1172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0304

Hom.:

902

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

Feb 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 15, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amelogenesis imperfecta type 1A

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

2.3

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

PromoterAI

-0.040

Neutral

(source)

Varity_R

0.36

gMVP

0.42

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over