rs190365795

Positions:

chr5-148118980-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006846.4(SPINK5):c.2241-6C>T 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 0.00732 in 1,613,660 control chromosomes in the GnomAD database, including 98 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 0.0079 ( 15 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 83 hom. )

Consequence

SPINK5
NM_006846.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002109

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0850

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 5-148118980-C-T is Benign according to our data. Variant chr5-148118980-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 351531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148118980-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00789 (1201/152260) while in subpopulation NFE AF= 0.00864 (588/68028). AF 95% confidence interval is 0.00807. There are 15 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2241-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.2241-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-25238G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00789

AC:

1201

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0435

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00864

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00810

AC:

2020

AN:

249300

Hom.:

AF XY:

0.00764

AC XY:

1033

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00735

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.00829

Gnomad OTH exome

AF:

0.00628

GnomAD4 exome

AF:

0.00726

AC:

10615

AN:

1461400

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

5193

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00662

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.0411

Gnomad4 NFE exome

AF:

0.00697

Gnomad4 OTH exome

AF:

0.00644

GnomAD4 genome

AF:

0.00789

AC:

1201

AN:

152260

Hom.:

Cov.:

AF XY:

0.00865

AC XY:

644

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0435

Gnomad4 NFE

AF:

0.00864

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00852

Hom.:

Bravo

AF:

0.00450

EpiCase

AF:

0.00785

EpiControl

AF:

0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	SPINK5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Netherton syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

-0.89

CADD

Benign

2.8

DANN

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0

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