1-209618670-A-AC

Variant names:

• chr1-209618670-A-AC
• rs397807887
• NM_000228.3:c.2702-12dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000228.3(LAMB3):​c.2702-12dupG variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.180
• Publications: 2 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 -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 VariationId 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 rank	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.2702-12dupG		intron_variant	Intron 18 of 22	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.2702-12dupG		intron_variant	Intron 18 of 22	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.2702-12dupG		intron_variant	Intron 18 of 22	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.2702-12dupG		intron_variant	Intron 17 of 21	1		ENSP00000375778.1
LAMB3	ENST00000455193.1	c.-104dupG		5_prime_UTR_variant	Exon 1 of 4	2		ENSP00000398683.1

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

GnomAD2 exomes AF: 0.957 AC: 237628 AN: 248192 AF XY: 0.957

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 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

African (AFR) AF: 0.991 AC: 33178 AN: 33476

American (AMR) AF: 0.982 AC: 43890 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 25477 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39687 AN: 39692

South Asian (SAS) AF: 0.988 AC: 85146 AN: 86202

European-Finnish (FIN) AF: 0.933 AC: 49641 AN: 53200

Middle Eastern (MID) AF: 0.989 AC: 5698 AN: 5764

European-Non Finnish (NFE) AF: 0.925 AC: 1028129 AN: 1111628

Other (OTH) AF: 0.944 AC: 56983 AN: 60346

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

African (AFR) AF: 0.988 AC: 41075 AN: 41584

American (AMR) AF: 0.975 AC: 14927 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 3379 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5169 AN: 5170

South Asian (SAS) AF: 0.990 AC: 4780 AN: 4830

European-Finnish (FIN) AF: 0.935 AC: 9937 AN: 10626

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63388 AN: 68032

Other (OTH) AF: 0.973 AC: 2054 AN: 2112

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Junctional epidermolysis bullosa Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs397807887; hg19: chr1-209792015;