rs3188691

Positions:

• chr5-148127020-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.2905A>G​(p.Lys969Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,724 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (20 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.187

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]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022529662).
• BP6: Variant 5-148127020-A-G is Benign according to our data. Variant chr5-148127020-A-G is described in ClinVar as [Benign]. Clinvar id is 351540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148127020-A-G is described in Lovd as [Benign]. Variant chr5-148127020-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00791 (1205/152300) while in subpopulation AFR AF= 0.0232 (966/41556). AF 95% confidence interval is 0.022. There are 11 homozygotes in gnomad4. There are 533 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.2905A>G	p.Lys969Glu	missense_variant	30/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.2905A>G	p.Lys969Glu	missense_variant	30/33	1	NM_006846.4	P2
SPINK5	ENST00000359874.7	c.2995A>G	p.Lys999Glu	missense_variant	31/34	1		A2
FBXO38-DT	ENST00000667608.1	n.1257-33278T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1205 AN: 152182 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.00252 AC: 627 AN: 249086 Hom.: 7 AF XY: 0.00208 AC XY: 281 AN XY: 135134

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00251

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00129 AC: 1884 AN: 1461424 Hom.: 20 Cov.: 30 AF XY: 0.00125 AC XY: 910 AN XY: 726976

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.000703

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00791 AC: 1205 AN: 152300 Hom.: 11 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74478

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00253 Hom.: 4

Bravo AF: 0.00849

ESP6500AA AF: 0.0225 AC: 81

ESP6500EA AF: 0.00147 AC: 12

ExAC AF: 0.00285 AC: 344

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 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
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.10	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.17	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.022
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MVP		0.21
MPC		0.14
ClinPred		0.00062	T
GERP RS		0.51
Varity_R		0.072
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs3188691; hg19: chr5-147506583;