rs115820034

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006846.4(SPINK5):c.2864T>C(p.Val955Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,614,214 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. V955L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 24 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.794

Publications

2 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041713417).

BP6

Variant 5-148125847-T-C is Benign according to our data. Variant chr5-148125847-T-C is described in ClinVar as Benign. ClinVar VariationId is 351538.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 = 0.0104 (1578/152342) while in subpopulation AFR AF = 0.0358 (1486/41558). AF 95% confidence interval is 0.0342. There are 35 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2864T>C	p.Val955Ala	missense	Exon 29 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.2954T>C	p.Val985Ala	missense	Exon 30 of 34	NP_001121170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2864T>C	p.Val955Ala	missense	Exon 29 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.2954T>C	p.Val985Ala	missense	Exon 30 of 34	ENSP00000352936.3
FBXO38-DT	ENST00000667608.1		n.1257-32105A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1575

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00263

AC:

655

AN:

249218

AF XY:

0.00198

show subpopulations

Gnomad AFR exome

AF:

0.0365

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.00108

AC:

1576

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000905

AC XY:

658

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0361

AC:

1210

AN:

33480

American (AMR)

AF:

0.00217

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000151

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000710

AC:

AN:

1111996

Other (OTH)

AF:

0.00281

AC:

170

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0104

AC:

1578

AN:

152342

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

784

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0358

AC:

1486

AN:

41558

American (AMR)

AF:

0.00457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0286

AC:

109

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00322

AC:

389

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis linearis circumflexa (1)

Netherton syndrome (1)

not provided (1)

SPINK5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

PhyloP100

0.79

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Uncertain

0.025

Sift4G

Uncertain

0.053

Polyphen

0.30

Vest4

0.21

MVP

0.27

MPC

0.12

ClinPred

0.0044

GERP RS

4.2

Varity_R

0.11

gMVP

0.20

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over