rs2076355

Positions:

• chr1-209638484-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000228.3(LAMB3):​c.298+50T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,231,534 control chromosomes in the GnomAD database, including 61,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7612 hom., cov: 33)
  • Exomes 𝑓: 0.29 (53547 hom.)
• Consequence: LAMB3 NM_000228.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.829

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-209638484-A-T is Benign according to our data. Variant chr1-209638484-A-T is described in ClinVar as [Benign]. Clinvar id is 255593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.298+50T>A		intron_variant		ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.298+50T>A		intron_variant		1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.298+50T>A		intron_variant		1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.298+50T>A		intron_variant		1		ENSP00000375778.1
LAMB3	ENST00000415782.1	c.298+50T>A		intron_variant		2		ENSP00000388960.1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45228 AN: 150420 Hom.: 7599 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.307

GnomAD3 exomes AF: 0.346 AC: 86095 AN: 249054 Hom.: 17777 AF XY: 0.344 AC XY: 46262 AN XY: 134676

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.714

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.294 AC: 317628 AN: 1080994 Hom.: 53547 Cov.: 15 AF XY: 0.298 AC XY: 165111 AN XY: 554946

Gnomad4 AFR exome AF: 0.317

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.710

Gnomad4 SAS exome AF: 0.472

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.301 AC: 45278 AN: 150540 Hom.: 7612 Cov.: 33 AF XY: 0.310 AC XY: 22807 AN XY: 73602

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.311

Alfa AF: 0.256 Hom.: 1051

Bravo AF: 0.313

Asia WGS AF: 0.575 AC: 1998 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2076355; hg19: chr1-209811829; COSMIC: COSV61915920;