5-148120328-G-T

Position:

chr5-148120328-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000256084.8(SPINK5):c.2475G>T(p.Glu825Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,603,508 control chromosomes in the GnomAD database, including 11,474 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1130 hom., cov: 31)

Exomes 𝑓: 0.10 ( 10344 hom. )

Consequence

SPINK5
ENST00000256084.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.623

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=0.004297644).

BP6

Variant 5-148120328-G-T is Benign according to our data. Variant chr5-148120328-G-T is described in ClinVar as [Benign]. Clinvar id is 139262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2475G>T	p.Glu825Asp	missense_variant	26/33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.2475G>T	p.Glu825Asp	missense_variant	26/33	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-26586C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16337

AN:

151894

Hom.:

1131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.0792

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.0873

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.129

AC:

30151

AN:

233340

Hom.:

2962

AF XY:

0.136

AC XY:

17138

AN XY:

125932

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0630

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.321

Gnomad SAS exome

AF:

0.292

Gnomad FIN exome

AF:

0.0806

Gnomad NFE exome

AF:

0.0815

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.0997

AC:

144722

AN:

1451500

Hom.:

10344

Cov.:

AF XY:

0.106

AC XY:

76379

AN XY:

720742

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.0659

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.292

Gnomad4 SAS exome

AF:

0.292

Gnomad4 FIN exome

AF:

0.0851

Gnomad4 NFE exome

AF:

0.0765

Gnomad4 OTH exome

AF:

0.114

GnomAD4 genome

AF:

0.107

AC:

16326

AN:

152008

Hom.:

1130

Cov.:

AF XY:

0.112

AC XY:

8295

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.0791

Gnomad4 ASJ

AF:

0.183

Gnomad4 EAS

AF:

0.309

Gnomad4 SAS

AF:

0.304

Gnomad4 FIN

AF:

0.0873

Gnomad4 NFE

AF:

0.0803

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.0908

Hom.:

1649

Bravo

AF:

0.104

TwinsUK

AF:

0.0734

AC:

272

ALSPAC

AF:

0.0698

AC:

269

ESP6500AA

AF:

0.107

AC:

397

ESP6500EA

AF:

0.0950

AC:

779

ExAC

AF:

0.128

AC:

15425

Asia WGS

AF:

0.241

AC:

836

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.0

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.46

T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;.;M

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.77

N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.016

B;B;.;B

Vest4

0.086

MutPred

0.14

Loss of methylation at K824 (P = 0.086);Loss of methylation at K824 (P = 0.086);.;Loss of methylation at K824 (P = 0.086);

MPC

0.11

ClinPred

0.0061

GERP RS

0.56

Varity_R

0.10

gMVP

0.23

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