rs1422991

Positions:

chr5-148099222-C-T

Variant summary

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

The NM_006846.4(SPINK5):c.1011-12C>T 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 0.509 in 1,600,236 control chromosomes in the GnomAD database, including 211,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 16753 hom., cov: 30)

Exomes 𝑓: 0.51 ( 195041 hom. )

Consequence

SPINK5
NM_006846.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000008578

Clinical Significance

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

Conservation

PhyloP100: -2.30

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=-0.91).

BP6

Variant 5-148099222-C-T is Benign according to our data. Variant chr5-148099222-C-T is described in ClinVar as [Benign]. Clinvar id is 260041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148099222-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.1011-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.1011-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006846.4	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-5480G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

68996

AN:

151548

Hom.:

16747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.509

Gnomad AMR

AF:

0.584

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.524

Gnomad OTH

AF:

0.479

GnomAD3 exomes

AF:

0.519

AC:

120595

AN:

232304

Hom.:

32368

AF XY:

0.517

AC XY:

64875

AN XY:

125530

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.699

Gnomad ASJ exome

AF:

0.461

Gnomad EAS exome

AF:

0.469

Gnomad SAS exome

AF:

0.485

Gnomad FIN exome

AF:

0.547

Gnomad NFE exome

AF:

0.515

Gnomad OTH exome

AF:

0.518

GnomAD4 exome

AF:

0.515

AC:

745988

AN:

1448572

Hom.:

195041

Cov.:

AF XY:

0.514

AC XY:

369723

AN XY:

719668

show subpopulations

Gnomad4 AFR exome

AF:

0.254

Gnomad4 AMR exome

AF:

0.683

Gnomad4 ASJ exome

AF:

0.461

Gnomad4 EAS exome

AF:

0.446

Gnomad4 SAS exome

AF:

0.489

Gnomad4 FIN exome

AF:

0.547

Gnomad4 NFE exome

AF:

0.521

Gnomad4 OTH exome

AF:

0.503

GnomAD4 genome

AF:

0.455

AC:

69017

AN:

151664

Hom.:

16753

Cov.:

AF XY:

0.459

AC XY:

34031

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.265

Gnomad4 AMR

AF:

0.584

Gnomad4 ASJ

AF:

0.455

Gnomad4 EAS

AF:

0.473

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.536

Gnomad4 NFE

AF:

0.524

Gnomad4 OTH

AF:

0.480

Alfa

AF:

0.477

Hom.:

3267

Bravo

AF:

0.454

Asia WGS

AF:

0.519

AC:

1799

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Netherton syndrome

Benign:1

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 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

-0.91

CADD

Benign

0.25

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000086

dbscSNV1_RF

Benign

0.0

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