rs2076355

Variant names:

• chr1-209638484-A-T
• rs2076355
• NM_000228.3:c.298+50T>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.298+50T>A		intron_variant	Intron 4 of 22	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.298+50T>A		intron_variant	Intron 4 of 22	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.298+50T>A		intron_variant	Intron 4 of 22	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.298+50T>A		intron_variant	Intron 3 of 21	1		ENSP00000375778.1
LAMB3	ENST00000415782.1	c.298+50T>A		intron_variant	Intron 4 of 5	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

GnomAD2 exomes AF: 0.346 AC: 86095 AN: 249054 AF XY: 0.344

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 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

African (AFR) AF: 0.317 AC: 8377 AN: 26400

American (AMR) AF: 0.496 AC: 21885 AN: 44100

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 5517 AN: 23802

East Asian (EAS) AF: 0.710 AC: 27081 AN: 38154

South Asian (SAS) AF: 0.472 AC: 37324 AN: 79062

European-Finnish (FIN) AF: 0.244 AC: 12975 AN: 53200

Middle Eastern (MID) AF: 0.274 AC: 1362 AN: 4966

European-Non Finnish (NFE) AF: 0.247 AC: 188292 AN: 763162

Other (OTH) AF: 0.308 AC: 14815 AN: 48148

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

African (AFR) AF: 0.322 AC: 12869 AN: 39984

American (AMR) AF: 0.405 AC: 6183 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 792 AN: 3470

East Asian (EAS) AF: 0.722 AC: 3729 AN: 5166

South Asian (SAS) AF: 0.489 AC: 2359 AN: 4826

European-Finnish (FIN) AF: 0.237 AC: 2511 AN: 10580

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15958 AN: 67950

Other (OTH) AF: 0.311 AC: 650 AN: 2092

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.70
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2076355; hg19: chr1-209811829; COSMIC: COSV61915920;