chr1-209622564-T-C

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.2673A>G(p.Leu891Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,810 control chromosomes in the GnomAD database, including 17,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1192 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16778 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.74

Publications

12 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=-0.59).

BP6

Variant 1-209622564-T-C is Benign according to our data. Variant chr1-209622564-T-C is described in ClinVar as Benign. ClinVar VariationId is 255589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.2673A>G	p.Leu891Leu	synonymous_variant	Exon 18 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.2673A>G	p.Leu891Leu	synonymous_variant	Exon 18 of 23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 link	c.2673A>G	p.Leu891Leu	synonymous_variant	Exon 18 of 23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 link	c.2673A>G	p.Leu891Leu	synonymous_variant	Exon 17 of 22	1		ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17443

AN:

151980

Hom.:

1193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0557

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.128

AC:

32185

AN:

251456

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.0526

Gnomad AMR exome

AF:

0.0744

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.146

AC:

213934

AN:

1461712

Hom.:

16778

Cov.:

AF XY:

0.149

AC XY:

108117

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0515

AC:

1725

AN:

33476

American (AMR)

AF:

0.0780

AC:

3487

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3672

AN:

26136

East Asian (EAS)

AF:

0.000428

AC:

AN:

39700

South Asian (SAS)

AF:

0.199

AC:

17177

AN:

86250

European-Finnish (FIN)

AF:

0.116

AC:

6219

AN:

53390

Middle Eastern (MID)

AF:

0.132

AC:

755

AN:

5714

European-Non Finnish (NFE)

AF:

0.155

AC:

172686

AN:

1111930

Other (OTH)

AF:

0.136

AC:

8196

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

11705

23409

35114

46818

58523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6026

12052

18078

24104

30130

<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:

0.115

AC:

17443

AN:

152098

Hom.:

1192

Cov.:

AF XY:

0.113

AC XY:

8434

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0558

AC:

2315

AN:

41518

American (AMR)

AF:

0.109

AC:

1658

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

462

AN:

3470

East Asian (EAS)

AF:

0.000776

AC:

AN:

5154

South Asian (SAS)

AF:

0.200

AC:

960

AN:

4812

European-Finnish (FIN)

AF:

0.114

AC:

1203

AN:

10596

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10445

AN:

67952

Other (OTH)

AF:

0.118

AC:

250

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

800

1600

2399

3199

3999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.142

Hom.:

2710

Bravo

AF:

0.109

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 22, 2015

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. -

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

- -

Feb 03, 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 12, 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

-0.59

CADD

Benign

3.4

(source)

DANN

Benign

0.73

PhyloP100

1.7

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