chr5-148107114-C-A

Variant names:

• chr5-148107114-C-A
• rs880687
• NM_006846.4:c.1557C>A

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.1557C>A​(p.Gly519Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,612,412 control chromosomes in the GnomAD database, including 213,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16395 hom., cov: 31)
  • Exomes 𝑓: 0.51 (196802 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.271

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=-0.49).
• BP6: Variant 5-148107114-C-A is Benign according to our data. Variant chr5-148107114-C-A is described in ClinVar as [Benign]. Clinvar id is 260047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148107114-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.271 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.1557C>A	p.Gly519Gly	synonymous_variant	Exon 17 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.1557C>A	p.Gly519Gly	synonymous_variant	Exon 17 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67528 AN: 151736 Hom.: 16385 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.473

GnomAD3 exomes AF: 0.520 AC: 129650 AN: 249522 Hom.: 35207 AF XY: 0.518 AC XY: 70121 AN XY: 135378

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.475

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.515 AC: 751623 AN: 1460560 Hom.: 196802 Cov.: 61 AF XY: 0.514 AC XY: 373182 AN XY: 726628

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.445 AC: 67549 AN: 151852 Hom.: 16395 Cov.: 31 AF XY: 0.449 AC XY: 33304 AN XY: 74194

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.455

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.524

Gnomad4 OTH AF: 0.475

Alfa AF: 0.511 Hom.: 35719

Bravo AF: 0.442

Asia WGS AF: 0.519 AC: 1800 AN: 3478

EpiCase AF: 0.518

EpiControl AF: 0.530

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Netherton syndrome Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.85
DANN	Benign	0.41

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: rs880687; hg19: chr5-147486677; COSMIC: COSV56248933;