1-209615169-G-A

Variant names:

• chr1-209615169-G-A
• rs2566
• NM_000228.3:c.*102C>T

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.*102C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,486,242 control chromosomes in the GnomAD database, including 57,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5835 hom., cov: 33)
  • Exomes 𝑓: 0.28 (51620 hom.)
• Consequence: LAMB3 NM_000228.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.14
• Publications: 47 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 1-209615169-G-A is Benign according to our data. Variant chr1-209615169-G-A is described in ClinVar as [Benign]. Clinvar id is 295059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.*102C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.*102C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.*102C>T		3_prime_UTR_variant	Exon 23 of 23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.*102C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41644 AN: 152008 Hom.: 5818 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.284

GnomAD4 exome AF: 0.275 AC: 367048 AN: 1334116 Hom.: 51620 Cov.: 19 AF XY: 0.273 AC XY: 182649 AN XY: 668618

African (AFR) AF: 0.253 AC: 7892 AN: 31136

American (AMR) AF: 0.412 AC: 17985 AN: 43666

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4610 AN: 24576

East Asian (EAS) AF: 0.337 AC: 13129 AN: 38972

South Asian (SAS) AF: 0.267 AC: 21916 AN: 81932

European-Finnish (FIN) AF: 0.276 AC: 12359 AN: 44730

Middle Eastern (MID) AF: 0.220 AC: 1200 AN: 5460

European-Non Finnish (NFE) AF: 0.271 AC: 272822 AN: 1007482

Other (OTH) AF: 0.269 AC: 15135 AN: 56162

GnomAD4 genome AF: 0.274 AC: 41703 AN: 152126 Hom.: 5835 Cov.: 33 AF XY: 0.274 AC XY: 20411 AN XY: 74366

African (AFR) AF: 0.248 AC: 10276 AN: 41498

American (AMR) AF: 0.352 AC: 5381 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3470

East Asian (EAS) AF: 0.347 AC: 1794 AN: 5170

South Asian (SAS) AF: 0.271 AC: 1309 AN: 4828

European-Finnish (FIN) AF: 0.265 AC: 2803 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18594 AN: 67984

Other (OTH) AF: 0.282 AC: 596 AN: 2112

Alfa AF: 0.272 Hom.: 16006

Bravo AF: 0.283

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20163849, 23320911) -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Junctional epidermolysis bullosa Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	9.4
DANN	Benign	0.50
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2566; hg19: chr1-209788514; COSMIC: COSV50521190; COSMIC: COSV50521190;