rs2228339

chr1-209650009-G-Achr1-209650009-G-Cchr1-209650009-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000228.3(LAMB3):c.138C>T(p.Thr46=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.665

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]

ACMG classification

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	UniProt
LAMB3	NM_000228.3	c.138C>T	p.Thr46=	synonymous_variant	3/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.138C>T	p.Thr46=	synonymous_variant	3/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.138C>T	p.Thr46=	synonymous_variant	3/23	1		P1
LAMB3	ENST00000391911.5	c.138C>T	p.Thr46=	synonymous_variant	2/22	1		P1
LAMB3	ENST00000415782.1	c.138C>T	p.Thr46=	synonymous_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38821 AN: 151992 Hom.: 5273 Cov.: 33

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

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.: 38 AF XY: 0.255 AC XY: 185586 AN XY: 727174

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.: 33 AF XY: 0.260 AC XY: 19352 AN XY: 74372

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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	11
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

Other links and lift over

dbSNP: rs2228339; hg19: chr1-209823354; COSMIC: COSV61915858;