NM_006846.4:c.3009T>C

Variant names:

• chr5-148131303-T-C
• rs2400478
• NM_006846.4:c.3009T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.3009T>C​(p.Gly1003Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,442 control chromosomes in the GnomAD database, including 298,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24691 hom., cov: 31)
  • Exomes 𝑓: 0.61 (273652 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.314

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 5-148131303-T-C is Benign according to our data. Variant chr5-148131303-T-C is described in ClinVar as [Benign]. Clinvar id is 260055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148131303-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.3009T>C	p.Gly1003Gly	synonymous_variant	Exon 31 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.3009T>C	p.Gly1003Gly	synonymous_variant	Exon 31 of 33	1	NM_006846.4	ENSP00000256084.7
SPINK5	ENST00000359874.7	c.3099T>C	p.Gly1033Gly	synonymous_variant	Exon 32 of 34	1		ENSP00000352936.3
FBXO38-DT	ENST00000667608.1	n.1257-37561A>G		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85275 AN: 151868 Hom.: 24656 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.559

GnomAD3 exomes AF: 0.599 AC: 149391 AN: 249530 Hom.: 45914 AF XY: 0.593 AC XY: 80273 AN XY: 135376

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.462

Gnomad SAS exome AF: 0.503

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.608 AC: 889275 AN: 1461456 Hom.: 273652 Cov.: 51 AF XY: 0.605 AC XY: 440042 AN XY: 727052

Gnomad4 AFR exome AF: 0.414

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.508

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.591

GnomAD4 genome AF: 0.562 AC: 85359 AN: 151986 Hom.: 24691 Cov.: 31 AF XY: 0.561 AC XY: 41694 AN XY: 74308

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.505

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.560

Alfa AF: 0.611 Hom.: 56249

Bravo AF: 0.558

Asia WGS AF: 0.536 AC: 1858 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.616

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -

not provided Benign:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ichthyosis linearis circumflexa Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Netherton syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.57
CADD	Benign	8.2
DANN	Benign	0.70

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: rs2400478; hg19: chr5-147510866; COSMIC: COSV56249075;