18-63804288-C-T

Position:

chr18-63804288-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_003784.4(SERPINB7):c.796C>T(p.Arg266Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,605,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SERPINB7
NM_003784.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 0.447

Variant links:

Genes affected

SERPINB7 (HGNC:13902): (serpin family B member 7) This gene encodes a member of a family of proteins which function as protease inhibitors. Expression of this gene is upregulated in IgA nephropathy and mutations have been found to cause palmoplantar keratoderma, Nagashima type. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SERPINB7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 0.304 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-63804288-C-T is Pathogenic according to our data. Variant chr18-63804288-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 102446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB7	NM_003784.4 linkuse as main transcript	c.796C>T	p.Arg266Ter	stop_gained	8/8	ENST00000398019.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB7	ENST00000398019.7 linkuse as main transcript	c.796C>T	p.Arg266Ter	stop_gained	8/8	1	NM_003784.4	P1	O75635-1
SERPINB7	ENST00000336429.6 linkuse as main transcript	c.796C>T	p.Arg266Ter	stop_gained	8/8	1		P1	O75635-1
SERPINB7	ENST00000546027.5 linkuse as main transcript	c.796C>T	p.Arg266Ter	stop_gained	8/8	2		P1	O75635-1
SERPINB7	ENST00000540675.5 linkuse as main transcript	c.745C>T	p.Arg249Ter	stop_gained	7/7	2			O75635-2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00848

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000550

AC:

134

AN:

243522

Hom.:

AF XY:

0.000510

AC XY:

AN XY:

131500

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00692

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000243

AC:

353

AN:

1452808

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

183

AN XY:

722538

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00764

Gnomad4 SAS exome

AF:

0.000190

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.000322

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00850

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000558

Hom.:

Bravo

AF:

0.000434

ExAC

AF:

0.000519

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Palmoplantar keratoderma, Nagashima type

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2021	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_003784.3:c.796C>T in the SERPINB7 gene has an allele frequency of 0.007 Asia in East Asian subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Palmoplantar keratoderma, nagashima type, compound heterozygous with c.218_219del2ins12, c.455-1G>A, respectively (PMID: 24207119). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102446, PMID:24207119, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000527, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	This sequence change in SERPINB7 is a nonsense variant predicted to cause a premature stop codon, p.(Arg266*), that is predicted to escape nonsense-mediated decay and remove <10% of the protein (removes amino acids 226-380) in a gene where loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.8% (347/44,860 alleles) in the East Asian population, which is higher than expected for a recessive disease. However, this variant is an East Asian founder mutation for Nagashima-type palmoplantar keratoderma. It has been reported in multiple affected individuals in the homozygous and compound heterozygous state (with at least one individual with a pathogenic variant on the second allele) and segregates with disease in at least one family (PMID: 24207119, 35178744). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Strong, PP1, BS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost, and other loss-of-function variants have been reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 24514002, 27786350, 27663160, 27569382, 27543371, 27506501, 28211129, 29888704, 30256384, 30581033, 30833958, 30004585, 32406097, 31980526, 24077912, 34426522, 33362511, 32892407, 33914963, 34379845, 27666198, 24207119, 24773080) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	This sequence change creates a premature translational stop signal (p.Arg266*) in the SERPINB7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the SERPINB7 protein. This variant is present in population databases (rs142859678, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Nagashima-type palmoplantar keratoderma (NPPK) (PMID: 24207119, 24514002, 27543371, 27666198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese and Han Chinese ancestry (PMID: 24514002, 24773080). ClinVar contains an entry for this variant (Variation ID: 102446). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

SERPINB7-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2023

The SERPINB7 c.796C>T variant is predicted to result in premature protein termination (p.Arg266*). This variant has been reported to be causative for autosomal recessive Nagashima-type palmoplantar keratosis and has been described as a founder mutation in Asian populations (Kubo et al. 2013. PubMed ID: 24207119; Yin et al. 2014. PubMed ID: 24514002; Zhang et al. 2016. PubMed ID: 27666198). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-61471522-C-T). Nonsense variants in SERPINB7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.061

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.69

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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