chr1-209615169-G-A

Position:

• chr1-209615169-G-A

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.*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

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 1-209615169-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/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.*102C>T		3_prime_UTR_variant	23/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.*102C>T		3_prime_UTR_variant	23/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.*102C>T		3_prime_UTR_variant	23/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.*102C>T		3_prime_UTR_variant	22/22	1		ENSP00000375778	P1

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

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.269

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

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.282

Alfa AF: 0.270 Hom.: 8903

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 20163849, 23320911) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

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	-0.82
CADD	Benign	9.4
DANN	Benign	0.50

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