rs5780528

Positions:

• chr1-209618670-A-AC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000228.3(LAMB3):​c.2702-12_2702-11insG variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,613,456 control chromosomes in the GnomAD database, including 710,496 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69774 hom., cov: 0)
  • Exomes 𝑓: 0.94 (640722 hom.)
• Consequence: LAMB3 NM_000228.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.180

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 -16 ACMG points.

• BP6: Variant 1-209618670-A-AC is Benign according to our data. Variant chr1-209618670-A-AC is described in ClinVar as [Benign]. Clinvar id is 255590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.2702-12_2702-11insG		splice_polypyrimidine_tract_variant, intron_variant		ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.2702-12_2702-11insG		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.2702-12_2702-11insG		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.2702-12_2702-11insG		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000375778	P1
LAMB3	ENST00000455193.1	c.-104_-103insG		5_prime_UTR_variant	1/4	2		ENSP00000398683

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145605 AN: 152222 Hom.: 69717 Cov.: 0

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.974

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.972

GnomAD3 exomes AF: 0.957 AC: 237628 AN: 248192 Hom.: 113846 AF XY: 0.957 AC XY: 128763 AN XY: 134494

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.983

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.988

Gnomad FIN exome AF: 0.935

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.961

GnomAD4 exome AF: 0.936 AC: 1367829 AN: 1461116 Hom.: 640722 Cov.: 34 AF XY: 0.938 AC XY: 681852 AN XY: 726846

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.982

Gnomad4 ASJ exome AF: 0.976

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.925

Gnomad4 OTH exome AF: 0.944

GnomAD4 genome AF: 0.957 AC: 145721 AN: 152340 Hom.: 69774 Cov.: 0 AF XY: 0.958 AC XY: 71334 AN XY: 74488

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.975

Gnomad4 ASJ AF: 0.974

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.990

Gnomad4 FIN AF: 0.935

Gnomad4 NFE AF: 0.932

Gnomad4 OTH AF: 0.973

Alfa AF: 0.945 Hom.: 15183

Bravo AF: 0.960

Asia WGS AF: 0.992 AC: 3449 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	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2016	Variant summary: The LAMB3 c.2702-12dupG variant involves the alteration of a non-conserved intronic nucleotide. Mutation Taster predicts a benign outcome for this variant. In addition, 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 114615/119804 control chromosomes (including 54857 homozygotes) at a frequency of 0.9566876, which is approximately 1027 times the estimated maximal expected allele frequency of a pathogenic LAMB3 variant (0.0009317), thus this variant is a benign polymorphism and allele dupG is the major allele at this cDNA position. In addition, a clinical diagnostic laboratory has also classified this variant as benign. Taken together, this variant is classified as Benign. -

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

Aug 19, 2021

- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Junctional epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397807887; hg19: chr1-209792015;