1-209628174-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000228.3(LAMB3):c.1149G>A(p.Pro383Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,561,816 control chromosomes in the GnomAD database, including 2,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P383P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 639 hom., cov: 33)

Exomes 𝑓: 0.019 ( 2269 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.90

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 1-209628174-C-T is Benign according to our data. Variant chr1-209628174-C-T is described in ClinVar as Benign. ClinVar VariationId is 255582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.1149G>A	p.Pro383Pro	synonymous_variant	Exon 11 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.1149G>A	p.Pro383Pro	synonymous_variant	Exon 11 of 23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 link	c.1149G>A	p.Pro383Pro	synonymous_variant	Exon 11 of 23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 link	c.1149G>A	p.Pro383Pro	synonymous_variant	Exon 10 of 22	1		ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes

AF:

0.0585

AC:

8897

AN:

152130

Hom.:

629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00310

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0611

AC:

10304

AN:

168724

AF XY:

0.0519

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.00231

Gnomad EAS exome

AF:

0.264

Gnomad FIN exome

AF:

0.00477

Gnomad NFE exome

AF:

0.00348

Gnomad OTH exome

AF:

0.0423

GnomAD4 exome

AF:

0.0185

AC:

26146

AN:

1409566

Hom.:

2269

Cov.:

AF XY:

0.0175

AC XY:

12209

AN XY:

696344

show subpopulations

African (AFR)

AF:

0.137

AC:

4393

AN:

32070

American (AMR)

AF:

0.182

AC:

6748

AN:

37162

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

25254

East Asian (EAS)

AF:

0.257

AC:

9391

AN:

36510

South Asian (SAS)

AF:

0.0150

AC:

1202

AN:

80314

European-Finnish (FIN)

AF:

0.00468

AC:

233

AN:

49736

Middle Eastern (MID)

AF:

0.0282

AC:

161

AN:

5710

European-Non Finnish (NFE)

AF:

0.00191

AC:

2073

AN:

1084410

Other (OTH)

AF:

0.0322

AC:

1882

AN:

58400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1595

3189

4784

6378

7973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.0587

AC:

8944

AN:

152250

Hom.:

639

Cov.:

AF XY:

0.0604

AC XY:

4499

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.127

AC:

5294

AN:

41526

American (AMR)

AF:

0.119

AC:

1821

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.258

AC:

1332

AN:

5158

South Asian (SAS)

AF:

0.0180

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00310

AC:

211

AN:

68018

Other (OTH)

AF:

0.0629

AC:

133

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

389

777

1166

1554

1943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0264

Hom.:

1123

Bravo

AF:

0.0748

Asia WGS

AF:

0.139

AC:

481

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.1

(source)

DANN

Benign

0.85

PhyloP100

-3.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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