rs144666367

chr18-63987003-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: 0.494

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM4: Stoplost variant in NM_002640.4 Downstream stopcodon found after 407 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB8	NM_002640.4	c.850C>T	p.Arg284Ter	stop_gained	7/7	ENST00000397985.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152164 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000633 AC XY: 86 AN XY: 135920

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.: 2 Cov.: 30 AF XY: 0.000457 AC XY: 332 AN XY: 727246

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: 58 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74468

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.: 1

Bravo AF: 0.000465

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peeling skin syndrome 5 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2023	- -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 2016	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.12	N
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

Other links and lift over

dbSNP: rs144666367; hg19: chr18-61654237; COSMIC: COSV54640353; COSMIC: COSV54640353;