1-209615147-G-A

Variant names:

• chr1-209615147-G-A
• rs185362831
• NM_000228.3:c.*124C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000228.3(LAMB3):​c.*124C>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 0.000262 in 1,219,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: LAMB3 NM_000228.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.120
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00125 (190/152250) while in subpopulation AFR AF = 0.00448 (186/41528). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.*124C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.*124C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_000228.3	ENSP00000348384.3
LAMB3	ENST00000367030.7	c.*124C>T		3_prime_UTR_variant	Exon 23 of 23	1		ENSP00000355997.3
LAMB3	ENST00000391911.5	c.*124C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000375778.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152132 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000122 AC: 130 AN: 1067718 Hom.: 1 Cov.: 14 AF XY: 0.0000867 AC XY: 47 AN XY: 542366

African (AFR) AF: 0.00428 AC: 112 AN: 26180

American (AMR) AF: 0.000198 AC: 8 AN: 40500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21602

East Asian (EAS) AF: 0.00 AC: 0 AN: 37168

South Asian (SAS) AF: 0.00 AC: 0 AN: 71906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 778860

Other (OTH) AF: 0.000211 AC: 10 AN: 47360

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152250 Hom.: 1 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74436

African (AFR) AF: 0.00448 AC: 186 AN: 41528

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00122

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		0.12

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

Other links and lift over

dbSNP: rs185362831; hg19: chr1-209788492;