rs2228339

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3 linkuse as main transcript	c.138C>T	p.Thr46Thr	synonymous_variant	3/23	ENST00000356082.9	NP_000219.2	Q13751A0A0S2Z3R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LAMB3	ENST00000356082.9 linkuse as main transcript	c.138C>T	p.Thr46Thr	synonymous_variant	3/23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 linkuse as main transcript	c.138C>T	p.Thr46Thr	synonymous_variant	3/23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 linkuse as main transcript	c.138C>T	p.Thr46Thr	synonymous_variant	2/22	1		ENSP00000375778.1	Q13751
LAMB3	ENST00000415782.1 linkuse as main transcript	c.138C>T	p.Thr46Thr	synonymous_variant	3/6	2		ENSP00000388960.1	Q5THA1

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

GnomAD3 exomes

AF:

0.285

AC:

71751

AN:

251336

Hom.:

11054

AF XY:

0.282

AC XY:

38328

AN XY:

135830

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 SAS exome

AF:

0.310

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

Gnomad4 AFR exome

AF:

0.218

Gnomad4 AMR exome

AF:

0.434

Gnomad4 ASJ exome

AF:

0.257

Gnomad4 EAS exome

AF:

0.330

Gnomad4 SAS exome

AF:

0.308

Gnomad4 FIN exome

AF:

0.237

Gnomad4 NFE exome

AF:

0.242

Gnomad4 OTH exome

AF:

0.260

GnomAD4 genome

AF:

0.256

AC:

38866

AN:

152110

Hom.:

5286

Cov.:

AF XY:

0.260

AC XY:

19352

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.378

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.330

Gnomad4 SAS

AF:

0.313

Gnomad4 FIN

AF:

0.235

Gnomad4 NFE

AF:

0.242

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.254

Hom.:

5162

Bravo

AF:

0.266

Asia WGS

AF:

0.319

AC:

1109

AN:

3478

EpiCase

AF:

0.252

EpiControl

AF:

0.256

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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 12, 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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.88

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