rs3764930

Positions:

• chr5-148125553-G-A

Variant summary

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

The NM_001127698.2(SPINK5):​c.2769G>A​(p.Ala923Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,138 control chromosomes in the GnomAD database, including 292,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22072 hom., cov: 32)
  • Exomes 𝑓: 0.60 (270590 hom.)
• Consequence: SPINK5 NM_001127698.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.607

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-148125553-G-A is Benign according to our data. Variant chr5-148125553-G-A is described in ClinVar as [Benign]. Clinvar id is 403487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148125553-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.607 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2740-170G>A		intron_variant		ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000359874.7	c.2769G>A	p.Ala923Ala	synonymous_variant	29/34	1		ENSP00000352936.3
SPINK5	ENST00000256084.8	c.2740-170G>A		intron_variant		1	NM_006846.4	ENSP00000256084.7
FBXO38-DT	ENST00000667608.1	n.1257-31811C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77786 AN: 151840 Hom.: 22060 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.520

GnomAD3 exomes AF: 0.585 AC: 145413 AN: 248372 Hom.: 44392 AF XY: 0.583 AC XY: 78619 AN XY: 134886

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.461

Gnomad SAS exome AF: 0.505

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.603 AC: 881185 AN: 1461180 Hom.: 270590 Cov.: 57 AF XY: 0.601 AC XY: 436558 AN XY: 726850

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.509

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.577

GnomAD4 genome AF: 0.512 AC: 77810 AN: 151958 Hom.: 22072 Cov.: 32 AF XY: 0.513 AC XY: 38112 AN XY: 74268

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.528

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.633

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.521

Alfa AF: 0.598 Hom.: 45188

Bravo AF: 0.501

Asia WGS AF: 0.522 AC: 1809 AN: 3478

EpiCase AF: 0.616

EpiControl AF: 0.615

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -
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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.25
DANN	Benign	0.51

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: rs3764930; hg19: chr5-147505116; COSMIC: COSV56249047; COSMIC: COSV56249047;