rs58888156

Positions:

chr5-148131249-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000256084.8(SPINK5):c.2965-10G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00748 in 1,613,150 control chromosomes in the GnomAD database, including 752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 407 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 345 hom. )

Consequence

SPINK5
ENST00000256084.8 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000009650

Clinical Significance

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

Conservation

PhyloP100: -0.234

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=-0.9).

BP6

Variant 5-148131249-G-C is Benign according to our data. Variant chr5-148131249-G-C is described in ClinVar as [Benign]. Clinvar id is 260054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2965-10G>C		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.2965-10G>C	splice_polypyrimidine_tract_variant, intron_variant	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
SPINK5	ENST00000359874.7 linkuse as main transcript	c.3055-10G>C	splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000352936	A2	Q9NQ38-3
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-37507C>G	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6006

AN:

152034

Hom.:

407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0104

AC:

2593

AN:

249500

Hom.:

176

AF XY:

0.00814

AC XY:

1102

AN XY:

135368

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.00741

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.00495

GnomAD4 exome

AF:

0.00415

AC:

6059

AN:

1460998

Hom.:

345

Cov.:

AF XY:

0.00352

AC XY:

2561

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.00868

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000235

Gnomad4 OTH exome

AF:

0.00971

GnomAD4 genome

AF:

0.0395

AC:

6014

AN:

152152

Hom.:

407

Cov.:

AF XY:

0.0386

AC XY:

2871

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0160

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0250

Alfa

AF:

0.0206

Hom.:

Bravo

AF:

0.0463

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Netherton syndrome

Benign:1

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

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.0

DANN

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000097

dbscSNV1_RF

Benign

0.0020

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

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