rs144666367

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PVS1_StrongPP5BS2

The NM_002640.4(SERPINB8):c.850C>T(p.Arg284*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

SERPINB8
NM_002640.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 0.494

Variant links:

Genes affected

SERPINB8 (HGNC:8952): (serpin family B member 8) The protein encoded by this gene is a member of the ov-serpin family of serine protease inhibitors. The encoded protein is produced by platelets and can bind to and inhibit the function of furin, a serine protease involved in platelet functions. In addition, this protein has been found to enhance the mechanical stability of cell-cell adhesion in the skin, and defects in this gene have been associated with an autosomal-recessive form of exfoliative ichthyosis. [provided by RefSeq, Jan 2017]

SERPINB8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.244 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 18-63987003-C-T is Pathogenic according to our data. Variant chr18-63987003-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254200.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB8	NM_002640.4 link	c.850C>T	p.Arg284*	stop_gained	Exon 7 of 7	ENST00000397985.7	NP_002631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB8	ENST00000397985.7 link	c.850C>T	p.Arg284*	stop_gained	Exon 7 of 7	1	NM_002640.4	ENSP00000381072.2		P50452-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000612

AC:

154

AN:

251494

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000459

AC:

671

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

332

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0000894

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0122

AC:

320

AN:

26136

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.000112

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.000246

AC:

274

AN:

1112008

Gnomad4 Remaining exome

AF:

0.00106

AC:

AN:

60396

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

AC:

0.0000481278

AN:

0.0000481278

Gnomad4 AMR

AF:

0.000131

AC:

0.000130787

AN:

0.000130787

Gnomad4 ASJ

AF:

0.00979

AC:

0.00979263

AN:

0.00979263

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000294

AC:

0.000294014

AN:

0.000294014

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000835

Hom.:

Bravo

AF:

0.000465

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peeling skin syndrome 5

Pathogenic:3Uncertain:1

Jan 04, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_002640.3:c.850C>T in the SERPINB8 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located in the last exon and may not lead to nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Peeling skin syndrome 5 in a pedigree, three homozygous c.850C>T, five carriers. And their parents are carriers (PMID: 27476651). The patient's phenotype is highly specific for SERPINB8 gene(PMID: 27476651). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Supporting; PP4; PP1_Strong. -

Sep 13, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 09, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg284*) in the SERPINB8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the SERPINB8 protein. This variant is present in population databases (rs144666367, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with exfoliative ichthyosis (PMID: 27476651). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254200). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.12

Vest4

0.097

GERP RS

5.7

Mutation Taster

=8/192

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over