chr5-148131303-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.3009T>C(p.Gly1003Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,442 control chromosomes in the GnomAD database, including 298,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24691 hom., cov: 31)

Exomes 𝑓: 0.61 ( 273652 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.314

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 5-148131303-T-C is Benign according to our data. Variant chr5-148131303-T-C is described in ClinVar as Benign. ClinVar VariationId is 260055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.314 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.3009T>C	p.Gly1003Gly	synonymous	Exon 31 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.3099T>C	p.Gly1033Gly	synonymous	Exon 32 of 34	NP_001121170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.3009T>C	p.Gly1003Gly	synonymous	Exon 31 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.3099T>C	p.Gly1033Gly	synonymous	Exon 32 of 34	ENSP00000352936.3
FBXO38-DT	ENST00000667608.1		n.1257-37561A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85275

AN:

151868

Hom.:

24656

Cov.:

show subpopulations

Gnomad AFR

AF:

0.419

Gnomad AMI

AF:

0.592

Gnomad AMR

AF:

0.649

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.504

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.629

Gnomad OTH

AF:

0.559

GnomAD2 exomes

AF:

0.599

AC:

149391

AN:

249530

AF XY:

0.593

show subpopulations

Gnomad AFR exome

AF:

0.418

Gnomad AMR exome

AF:

0.746

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.462

Gnomad FIN exome

AF:

0.642

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.598

GnomAD4 exome

AF:

0.608

AC:

889275

AN:

1461456

Hom.:

273652

Cov.:

AF XY:

0.605

AC XY:

440042

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.414

AC:

13873

AN:

33472

American (AMR)

AF:

0.732

AC:

32719

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

14369

AN:

26130

East Asian (EAS)

AF:

0.437

AC:

17339

AN:

39670

South Asian (SAS)

AF:

0.508

AC:

43782

AN:

86250

European-Finnish (FIN)

AF:

0.642

AC:

34263

AN:

53394

Middle Eastern (MID)

AF:

0.536

AC:

3092

AN:

5766

European-Non Finnish (NFE)

AF:

0.624

AC:

694182

AN:

1111674

Other (OTH)

AF:

0.591

AC:

35656

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

20111

40222

60332

80443

100554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18454

36908

55362

73816

92270

<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:

0.562

AC:

85359

AN:

151986

Hom.:

24691

Cov.:

AF XY:

0.561

AC XY:

41694

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.420

AC:

17390

AN:

41416

American (AMR)

AF:

0.649

AC:

9909

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1874

AN:

3468

East Asian (EAS)

AF:

0.470

AC:

2424

AN:

5162

South Asian (SAS)

AF:

0.505

AC:

2437

AN:

4822

European-Finnish (FIN)

AF:

0.632

AC:

6672

AN:

10560

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.629

AC:

42779

AN:

67976

Other (OTH)

AF:

0.560

AC:

1181

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1862

3723

5585

7446

9308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.601

Hom.:

83704

Bravo

AF:

0.558

Asia WGS

AF:

0.536

AC:

1858

AN:

3478

EpiCase

AF:

0.617

EpiControl

AF:

0.616

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported.

not provided

Benign:1Other:1

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.

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.2

(source)

DANN

Benign

0.70

PhyloP100

0.31

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over