dbSNP rs2228339: LAMB3:p.Thr46Thr (chr1-209650009-G-A) – ACMG Classification: Benign (-21 pts)

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.138C>T(p.Thr46Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,613,834 control chromosomes in the GnomAD database, including 54,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5286 hom., cov: 33)

Exomes 𝑓: 0.25 ( 49232 hom. )

Consequence

LAMB3
NM_000228.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.665

Publications

13 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=-0.51).

BP6

Variant 1-209650009-G-A is Benign according to our data. Variant chr1-209650009-G-A is described in ClinVar as Benign. ClinVar VariationId is 255584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.665 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000228.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMB3	NM_000228.3	MANE Select	c.138C>T	p.Thr46Thr	synonymous	Exon 3 of 23	NP_000219.2
LAMB3	NM_001017402.2		c.138C>T	p.Thr46Thr	synonymous	Exon 2 of 22	NP_001017402.1
LAMB3	NM_001127641.1		c.138C>T	p.Thr46Thr	synonymous	Exon 3 of 23	NP_001121113.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LAMB3	ENST00000356082.9	TSL:1 MANE Select	c.138C>T	p.Thr46Thr	synonymous	Exon 3 of 23	ENSP00000348384.3
LAMB3	ENST00000367030.7	TSL:1	c.138C>T	p.Thr46Thr	synonymous	Exon 3 of 23	ENSP00000355997.3
LAMB3	ENST00000391911.5	TSL:1	c.138C>T	p.Thr46Thr	synonymous	Exon 2 of 22	ENSP00000375778.1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38821

AN:

151992

Hom.:

5273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.264

GnomAD2 exomes

AF:

0.285

AC:

71751

AN:

251336

AF XY:

0.282

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.440

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.332

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.244

Gnomad OTH exome

AF:

0.287

GnomAD4 exome

AF:

0.254

AC:

372001

AN:

1461724

Hom.:

49232

Cov.:

AF XY:

0.255

AC XY:

185586

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.218

AC:

7293

AN:

33480

American (AMR)

AF:

0.434

AC:

19416

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6728

AN:

26134

East Asian (EAS)

AF:

0.330

AC:

13098

AN:

39698

South Asian (SAS)

AF:

0.308

AC:

26576

AN:

86258

European-Finnish (FIN)

AF:

0.237

AC:

12668

AN:

53402

Middle Eastern (MID)

AF:

0.265

AC:

1526

AN:

5768

European-Non Finnish (NFE)

AF:

0.242

AC:

269011

AN:

1111870

Other (OTH)

AF:

0.260

AC:

15685

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16927

33854

50782

67709

84636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9354

18708

28062

37416

46770

<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:

0.256

AC:

38866

AN:

152110

Hom.:

5286

Cov.:

AF XY:

0.260

AC XY:

19352

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.224

AC:

9273

AN:

41490

American (AMR)

AF:

0.378

AC:

5777

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

895

AN:

3472

East Asian (EAS)

AF:

0.330

AC:

1695

AN:

5130

South Asian (SAS)

AF:

0.313

AC:

1511

AN:

4820

European-Finnish (FIN)

AF:

0.235

AC:

2496

AN:

10600

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16466

AN:

67996

Other (OTH)

AF:

0.266

AC:

560

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1447

2894

4340

5787

7234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.256

Hom.:

6813

Bravo

AF:

0.266

Asia WGS

AF:

0.319

AC:

1109

AN:

3478

EpiCase

AF:

0.252

EpiControl

AF:

0.256

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Amelogenesis imperfecta type 1A (1)

Junctional epidermolysis bullosa (1)

Junctional epidermolysis bullosa gravis of Herlitz (1)

Junctional epidermolysis bullosa, non-Herlitz type (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.67

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over