rs180955184

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000256084.8(SPINK5):c.2667-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,583,566 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 44 hom. )

Consequence

SPINK5
ENST00000256084.8 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004642

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.364

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 5-148124761-G-A is Benign according to our data. Variant chr5-148124761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148124761-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2667-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.2667-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
SPINK5	ENST00000359874.7 linkuse as main transcript	c.2667-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000352936	A2	Q9NQ38-3
SPINK5	ENST00000398454.5 linkuse as main transcript	c.2667-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000381472		Q9NQ38-2
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-31019C>T	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00512

AC:

759

AN:

148384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000372

Gnomad AMI

AF:

0.00991

Gnomad AMR

AF:

0.000473

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00212

Gnomad FIN

AF:

0.0454

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00343

GnomAD3 exomes

AF:

0.00567

AC:

1309

AN:

231018

Hom.:

AF XY:

0.00573

AC XY:

717

AN XY:

125214

show subpopulations

Gnomad AFR exome

AF:

0.000359

Gnomad AMR exome

AF:

0.000400

Gnomad ASJ exome

AF:

0.000528

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.00532

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00416

AC:

5977

AN:

1435076

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

2963

AN XY:

713384

show subpopulations

Gnomad4 AFR exome

AF:

0.000430

Gnomad4 AMR exome

AF:

0.000354

Gnomad4 ASJ exome

AF:

0.000866

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00201

Gnomad4 FIN exome

AF:

0.0314

Gnomad4 NFE exome

AF:

0.00360

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00511

AC:

759

AN:

148490

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

488

AN XY:

72112

show subpopulations

Gnomad4 AFR

AF:

0.000370

Gnomad4 AMR

AF:

0.000472

Gnomad4 ASJ

AF:

0.00116

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00212

Gnomad4 FIN

AF:

0.0454

Gnomad4 NFE

AF:

0.00420

Gnomad4 OTH

AF:

0.00339

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SPINK5: BP4, BS2 -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Netherton syndrome

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.1

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000046

dbscSNV1_RF

Benign

0.0040

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

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