rs3764930

Variant names:

• chr5-148125553-G-A
• rs3764930
• ENST00000359874.7:c.2769G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148125553-G-A
• chr5-148125553-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000359874.7(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 ENST00000359874.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.607
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 403487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2740-170G>A		intron_variant	Intron 28 of 32	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000359874.7	c.2769G>A	p.Ala923Ala	synonymous_variant	Exon 29 of 34	1		ENSP00000352936.3
SPINK5	ENST00000256084.8	c.2740-170G>A		intron_variant	Intron 28 of 32	1	NM_006846.4	ENSP00000256084.7
FBXO38-DT	ENST00000667608.1	n.1257-31811C>T		intron_variant	Intron 3 of 4

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

GnomAD2 exomes AF: 0.585 AC: 145413 AN: 248372 AF XY: 0.583

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 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

African (AFR) AF: 0.233 AC: 7794 AN: 33474

American (AMR) AF: 0.720 AC: 32160 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14083 AN: 26128

East Asian (EAS) AF: 0.438 AC: 17384 AN: 39688

South Asian (SAS) AF: 0.509 AC: 43880 AN: 86226

European-Finnish (FIN) AF: 0.642 AC: 34261 AN: 53388

Middle Eastern (MID) AF: 0.524 AC: 3023 AN: 5766

European-Non Finnish (NFE) AF: 0.624 AC: 693794 AN: 1111468

Other (OTH) AF: 0.577 AC: 34806 AN: 60366

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

African (AFR) AF: 0.249 AC: 10302 AN: 41432

American (AMR) AF: 0.629 AC: 9591 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1830 AN: 3468

East Asian (EAS) AF: 0.471 AC: 2422 AN: 5144

South Asian (SAS) AF: 0.506 AC: 2443 AN: 4824

European-Finnish (FIN) AF: 0.633 AC: 6696 AN: 10570

Middle Eastern (MID) AF: 0.524 AC: 152 AN: 290

European-Non Finnish (NFE) AF: 0.629 AC: 42734 AN: 67950

Other (OTH) AF: 0.521 AC: 1100 AN: 2110

Alfa AF: 0.590 Hom.: 54226

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

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. -

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 -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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