rs6892205

Positions:

Variant summary

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

The NM_006846.4(SPINK5):c.800A>G(p.Gln267Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,607,930 control chromosomes in the GnomAD database, including 215,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q267H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.51 ( 19668 hom., cov: 31)

Exomes 𝑓: 0.52 ( 195529 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -3.98

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=5.1259713E-6).

BP6

Variant 5-148095823-A-G is Benign according to our data. Variant chr5-148095823-A-G is described in ClinVar as [Benign]. Clinvar id is 139256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148095823-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.800A>G	p.Gln267Arg	missense_variant	10/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.800A>G	p.Gln267Arg	missense_variant	10/33	1	NM_006846.4	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-2081T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76829

AN:

151480

Hom.:

19656

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.605

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.489

Gnomad FIN

AF:

0.533

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.521

GnomAD3 exomes

AF:

0.532

AC:

132330

AN:

248824

Hom.:

36082

AF XY:

0.526

AC XY:

71018

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.459

Gnomad AMR exome

AF:

0.709

Gnomad ASJ exome

AF:

0.457

Gnomad EAS exome

AF:

0.478

Gnomad SAS exome

AF:

0.486

Gnomad FIN exome

AF:

0.546

Gnomad NFE exome

AF:

0.513

Gnomad OTH exome

AF:

0.527

GnomAD4 exome

AF:

0.515

AC:

750408

AN:

1456332

Hom.:

195529

Cov.:

AF XY:

0.513

AC XY:

372040

AN XY:

724698

show subpopulations

Gnomad4 AFR exome

AF:

0.454

Gnomad4 AMR exome

AF:

0.695

Gnomad4 ASJ exome

AF:

0.456

Gnomad4 EAS exome

AF:

0.451

Gnomad4 SAS exome

AF:

0.487

Gnomad4 FIN exome

AF:

0.545

Gnomad4 NFE exome

AF:

0.515

Gnomad4 OTH exome

AF:

0.512

GnomAD4 genome

AF:

0.507

AC:

76871

AN:

151598

Hom.:

19668

Cov.:

AF XY:

0.510

AC XY:

37743

AN XY:

74066

show subpopulations

Gnomad4 AFR

AF:

0.458

Gnomad4 AMR

AF:

0.605

Gnomad4 ASJ

AF:

0.449

Gnomad4 EAS

AF:

0.475

Gnomad4 SAS

AF:

0.491

Gnomad4 FIN

AF:

0.533

Gnomad4 NFE

AF:

0.518

Gnomad4 OTH

AF:

0.521

Alfa

AF:

0.514

Hom.:

41148

Bravo

AF:

0.514

TwinsUK

AF:

0.526

AC:

1952

ALSPAC

AF:

0.521

AC:

2008

ESP6500AA

AF:

0.460

AC:

1667

ESP6500EA

AF:

0.508

AC:

4132

ExAC

AF:

0.521

AC:

62900

Asia WGS

AF:

0.533

AC:

1846

AN:

3476

EpiCase

AF:

0.514

EpiControl

AF:

0.524

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 75. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Netherton syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

DANN

Benign

0.12

DEOGEN2

Benign

0.027

.;.;.;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.17

T;T;T;T

MetaRNN

Benign

0.0000051

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.59

N;N;.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.22

PROVEAN

Benign

0.090

N;N;N;N

REVEL

Benign

0.047

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.019

MPC

0.10

ClinPred

0.0035

GERP RS

-7.6

Varity_R

0.051

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