chr5-148089550-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.531G>A(p.Arg177Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,612,058 control chromosomes in the GnomAD database, including 833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 106 hom., cov: 32)

Exomes 𝑓: 0.022 ( 727 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.251

Publications

5 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:

LOC124901185 (HGNC:):

LOC124901185 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 5-148089550-G-A is Benign according to our data. Variant chr5-148089550-G-A is described in ClinVar as Benign. ClinVar VariationId is 139255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.251 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.531G>A	p.Arg177Arg	synonymous_variant	Exon 7 of 33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.531G>A	p.Arg177Arg	synonymous_variant	Exon 7 of 33	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0292

AC:

4429

AN:

151700

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0501

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.0452

Gnomad SAS

AF:

0.0939

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0313

AC:

7800

AN:

248882

AF XY:

0.0337

show subpopulations

Gnomad AFR exome

AF:

0.0508

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.0508

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0223

AC:

32509

AN:

1460240

Hom.:

727

Cov.:

AF XY:

0.0245

AC XY:

17822

AN XY:

726450

show subpopulations

African (AFR)

AF:

0.0505

AC:

1684

AN:

33366

American (AMR)

AF:

0.0141

AC:

631

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

721

AN:

26046

East Asian (EAS)

AF:

0.0343

AC:

1361

AN:

39662

South Asian (SAS)

AF:

0.0933

AC:

8043

AN:

86230

European-Finnish (FIN)

AF:

0.0114

AC:

608

AN:

53420

Middle Eastern (MID)

AF:

0.0278

AC:

160

AN:

5752

European-Non Finnish (NFE)

AF:

0.0160

AC:

17762

AN:

1110890

Other (OTH)

AF:

0.0255

AC:

1539

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2108

4216

6324

8432

10540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.0291

AC:

4425

AN:

151818

Hom.:

106

Cov.:

AF XY:

0.0289

AC XY:

2148

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.0500

AC:

2072

AN:

41440

American (AMR)

AF:

0.0148

AC:

225

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3464

East Asian (EAS)

AF:

0.0449

AC:

229

AN:

5100

South Asian (SAS)

AF:

0.0934

AC:

450

AN:

4820

European-Finnish (FIN)

AF:

0.0128

AC:

136

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1144

AN:

67850

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

214

428

642

856

1070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0223

Hom.:

Bravo

AF:

0.0295

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0179

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Ichthyosis linearis circumflexa

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Netherton syndrome

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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