rs2179402

chr1-209625908-A-Gchr1-209625908-A-T

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.1716T>C(p.Cys572=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 1,613,420 control chromosomes in the GnomAD database, including 441,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42713 hom., cov: 35)
  • Exomes 𝑓: 0.74 (398928 hom.)
• Consequence: LAMB3 NM_000228.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.966

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=-0.74).
• BP6: Variant 1-209625908-A-G is Benign according to our data. Variant chr1-209625908-A-G is described in ClinVar as [Benign]. Clinvar id is 255587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209625908-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.966 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB3	NM_000228.3	c.1716T>C	p.Cys572=	synonymous_variant	14/23	ENST00000356082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB3	ENST00000356082.9	c.1716T>C	p.Cys572=	synonymous_variant	14/23	1	NM_000228.3	P1
LAMB3	ENST00000367030.7	c.1716T>C	p.Cys572=	synonymous_variant	14/23	1		P1
LAMB3	ENST00000391911.5	c.1716T>C	p.Cys572=	synonymous_variant	13/22	1		P1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113899 AN: 152116 Hom.: 42675 Cov.: 35

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.745

GnomAD3 exomes AF: 0.754 AC: 187810 AN: 249024 Hom.: 70965 AF XY: 0.753 AC XY: 101513 AN XY: 134892

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.823

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.738 AC: 1078370 AN: 1461186 Hom.: 398928 Cov.: 79 AF XY: 0.739 AC XY: 536973 AN XY: 726910

Gnomad4 AFR exome AF: 0.768

Gnomad4 AMR exome AF: 0.769

Gnomad4 ASJ exome AF: 0.824

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.742

Gnomad4 FIN exome AF: 0.730

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.749 AC: 113992 AN: 152234 Hom.: 42713 Cov.: 35 AF XY: 0.751 AC XY: 55894 AN XY: 74416

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.752

Gnomad4 ASJ AF: 0.814

Gnomad4 EAS AF: 0.823

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.740

Gnomad4 NFE AF: 0.727

Gnomad4 OTH AF: 0.746

Alfa AF: 0.739 Hom.: 53295

Bravo AF: 0.751

Asia WGS AF: 0.736 AC: 2560 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Junctional epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.74
Cadd	Benign	0.27
Dann	Benign	0.56

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: rs2179402; hg19: chr1-209799253; COSMIC: COSV61918520; COSMIC: COSV61918520;