rs35121983

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006846.4(SPINK5):c.531G>A(p.Arg177=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,612,058 control chromosomes in the GnomAD database, including 833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 106 hom., cov: 32)

Exomes 𝑓: 0.022 ( 727 hom. )

Consequence

SPINK5
NM_006846.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.251

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:

LOC124901185 (HGNC:):

LOC124901185 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 5-148089550-G-A is Benign according to our data. Variant chr5-148089550-G-A is described in ClinVar as [Benign]. Clinvar id is 139255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.251 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0862 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.531G>A	p.Arg177=	synonymous_variant	7/33	ENST00000256084.8	NP_006837.2
LOC124901185	XR_007059139.1 linkuse as main transcript	n.415C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.531G>A	p.Arg177=	synonymous_variant	7/33	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1671C>T		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes

AF:

0.0292

AC:

4429

AN:

151700

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0501

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.0452

Gnomad SAS

AF:

0.0939

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0316

GnomAD3 exomes

AF:

0.0313

AC:

7800

AN:

248882

Hom.:

215

AF XY:

0.0337

AC XY:

4549

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.0508

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.0508

Gnomad SAS exome

AF:

0.0935

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0223

AC:

32509

AN:

1460240

Hom.:

727

Cov.:

AF XY:

0.0245

AC XY:

17822

AN XY:

726450

show subpopulations

Gnomad4 AFR exome

AF:

0.0505

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.0277

Gnomad4 EAS exome

AF:

0.0343

Gnomad4 SAS exome

AF:

0.0933

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.0160

Gnomad4 OTH exome

AF:

0.0255

GnomAD4 genome

AF:

0.0291

AC:

4425

AN:

151818

Hom.:

106

Cov.:

AF XY:

0.0289

AC XY:

2148

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.0500

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.0449

Gnomad4 SAS

AF:

0.0934

Gnomad4 FIN

AF:

0.0128

Gnomad4 NFE

AF:

0.0169

Gnomad4 OTH

AF:

0.0313

Alfa

AF:

0.0222

Hom.:

Bravo

AF:

0.0295

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0179

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

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