chr5-148127030-A-G

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.2915A>G(p.His972Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,624 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. H972Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 67 hom., cov: 32)

Exomes 𝑓: 0.030 ( 789 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

Publications

14 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=0.0027019978).

BP6

Variant 5-148127030-A-G is Benign according to our data. Variant chr5-148127030-A-G is described in ClinVar as Benign. ClinVar VariationId is 351541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0236 (3592/152290) while in subpopulation NFE AF = 0.0333 (2267/68014). AF 95% confidence interval is 0.0322. There are 67 homozygotes in GnomAd4. There are 1771 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 67 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2915A>G	p.His972Arg	missense_variant	Exon 30 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPINK5	ENST00000256084.8 link	c.2915A>G	p.His972Arg	missense_variant	Exon 30 of 33	1	NM_006846.4	ENSP00000256084.7
SPINK5	ENST00000359874.7 link	c.3005A>G	p.His1002Arg	missense_variant	Exon 31 of 34	1		ENSP00000352936.3
FBXO38-DT	ENST00000667608.1 link	n.1257-33288T>C		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3592

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00661

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0259

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.0451

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0241

AC:

5995

AN:

249152

AF XY:

0.0239

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0331

Gnomad OTH exome

AF:

0.0221

GnomAD4 exome

AF:

0.0301

AC:

43934

AN:

1461334

Hom.:

789

Cov.:

AF XY:

0.0294

AC XY:

21338

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.00439

AC:

147

AN:

33476

American (AMR)

AF:

0.0154

AC:

687

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0249

AC:

650

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.00984

AC:

848

AN:

86196

European-Finnish (FIN)

AF:

0.0469

AC:

2501

AN:

53380

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0337

AC:

37452

AN:

1111662

Other (OTH)

AF:

0.0268

AC:

1620

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

2029

4058

6088

8117

10146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1384

2768

4152

5536

6920

<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:

0.0236

AC:

3592

AN:

152290

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1771

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00659

AC:

274

AN:

41568

American (AMR)

AF:

0.0258

AC:

394

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00913

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0451

AC:

478

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0333

AC:

2267

AN:

68014

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

181

362

543

724

905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0289

Hom.:

254

Bravo

AF:

0.0203

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.00693

AC:

ESP6500EA

AF:

0.0309

AC:

252

ExAC

AF:

0.0236

AC:

2854

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0282

EpiControl

AF:

0.0282

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Netherton syndrome

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ichthyosis linearis circumflexa

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.6

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L

PhyloP100

1.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.040

Sift

Benign

0.49

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.22

B;B

Vest4

0.070

MPC

0.32

ClinPred

0.013

GERP RS

2.9

Varity_R

0.060

gMVP

0.30

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over