Variant rs144666367 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002640.4(SERPINB8):c.850C>T(p.Arg284Ter) 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 Uncertain significance (★★).

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

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U: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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB8	NM_002640.4 linkuse as main transcript	c.850C>T	p.Arg284Ter	stop_gained	7/7	ENST00000397985.7	NP_002631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB8	ENST00000397985.7 linkuse as main transcript	c.850C>T	p.Arg284Ter	stop_gained	7/7	1	NM_002640.4	ENSP00000381072	P1	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

GnomAD3 exomes

AF:

0.000612

AC:

154

AN:

251494

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135920

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 SAS 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

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.00106

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

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000904

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: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peeling skin syndrome 5

Pathogenic:2Uncertain:1

Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2021

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, ExAC 0.09%). 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

MutationTaster

Benign

1.0

D;D;D

Vest4

0.097

GERP RS

5.7

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