chr1-209622564-T-C

Position:

• chr1-209622564-T-C

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.2673A>G​(p.Leu891Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,810 control chromosomes in the GnomAD database, including 17,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1192 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16778 hom.)
• Consequence: LAMB3 NM_000228.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.74

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=-0.59).
• BP6: Variant 1-209622564-T-C is Benign according to our data. Variant chr1-209622564-T-C is described in ClinVar as [Benign]. Clinvar id is 255589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.2673A>G	p.Leu891Leu	synonymous_variant	18/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.2673A>G	p.Leu891Leu	synonymous_variant	18/23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.2673A>G	p.Leu891Leu	synonymous_variant	18/23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.2673A>G	p.Leu891Leu	synonymous_variant	17/22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17443 AN: 151980 Hom.: 1193 Cov.: 32

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.128 AC: 32185 AN: 251456 Hom.: 2527 AF XY: 0.137 AC XY: 18562 AN XY: 135904

Gnomad AFR exome AF: 0.0526

Gnomad AMR exome AF: 0.0744

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.146 AC: 213934 AN: 1461712 Hom.: 16778 Cov.: 34 AF XY: 0.149 AC XY: 108117 AN XY: 727168

Gnomad4 AFR exome AF: 0.0515

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.115 AC: 17443 AN: 152098 Hom.: 1192 Cov.: 32 AF XY: 0.113 AC XY: 8434 AN XY: 74334

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.118

Alfa AF: 0.145 Hom.: 2170

Bravo AF: 0.109

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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	-0.59
CADD	Benign	3.4
DANN	Benign	0.73

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: rs3179860; hg19: chr1-209795909; COSMIC: COSV61915903; COSMIC: COSV61915903;