rs2303064

chr5-148100517-G-Achr5-148100517-G-Cchr5-148100517-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):c.1156G>A(p.Asp386Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,950 control chromosomes in the GnomAD database, including 30,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6884 hom., cov: 32)
  • Exomes 𝑓: 0.15 (23885 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.67

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=0.0070517957).
• BP6: Variant 5-148100517-G-A is Benign according to our data. Variant chr5-148100517-G-A is described in ClinVar as [Benign]. Clinvar id is 139258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148100517-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.1156G>A	p.Asp386Asn	missense_variant	13/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.1156G>A	p.Asp386Asn	missense_variant	13/33	1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1257-6775C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37827 AN: 151836 Hom.: 6874 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.204 AC: 50931 AN: 249156 Hom.: 7514 AF XY: 0.205 AC XY: 27699 AN XY: 135164

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.450

Gnomad SAS exome AF: 0.356

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.151 AC: 220585 AN: 1460996 Hom.: 23885 Cov.: 44 AF XY: 0.156 AC XY: 113573 AN XY: 726812

Gnomad4 AFR exome AF: 0.504

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.464

Gnomad4 SAS exome AF: 0.353

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.249 AC: 37869 AN: 151954 Hom.: 6884 Cov.: 32 AF XY: 0.254 AC XY: 18848 AN XY: 74266

Gnomad4 AFR AF: 0.497

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.225

Alfa AF: 0.151 Hom.: 6205

Bravo AF: 0.259

TwinsUK AF: 0.105 AC: 391

ALSPAC AF: 0.107 AC: 413

ESP6500AA AF: 0.458 AC: 1800

ESP6500EA AF: 0.125 AC: 1044

ExAC AF: 0.212 AC: 25584

Asia WGS AF: 0.348 AC: 1211 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -
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. -

Netherton syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.0071	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.086	T;D;T;D
Polyphen		0.40	B;P;.;P
Vest4		0.23
MPC		0.21
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.32

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: rs2303064; hg19: chr5-147480080; COSMIC: COSV56250524; COSMIC: COSV56250524;