rs115504632

Positions:

chr5-148107109-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006846.4(SPINK5):c.1552C>T(p.Arg518Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,382 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 18 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.408

Variant links:

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SPINK5 links:

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

FBXO38-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013533473).

BP6

Variant 5-148107109-C-T is Benign according to our data. Variant chr5-148107109-C-T is described in ClinVar as [Benign]. Clinvar id is 139260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00969 (1474/152194) while in subpopulation AFR AF= 0.0336 (1394/41542). AF 95% confidence interval is 0.0321. There are 19 homozygotes in gnomad4. There are 668 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.1552C>T	p.Arg518Cys	missense_variant	17/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.1552C>T	p.Arg518Cys	missense_variant	17/33	1	NM_006846.4	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-13367G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00967

AC:

1471

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

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:

0.000118

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00244

AC:

610

AN:

249520

Hom.:

AF XY:

0.00169

AC XY:

229

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.0344

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00100

AC:

1467

AN:

1461188

Hom.:

Cov.:

AF XY:

0.000830

AC XY:

603

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0355

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00969

AC:

1474

AN:

152194

Hom.:

Cov.:

AF XY:

0.00898

AC XY:

668

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0336

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.0111

ESP6500AA

AF:

0.0255

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00281

AC:

340

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Netherton syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

.;.;.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.64

T;T;T;T

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.045

N;N;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

2.9

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.10

T;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.47

MVP

0.27

MPC

0.44

ClinPred

0.033

GERP RS

0.77

Varity_R

0.088

gMVP

0.38

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

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