rs3756688

Positions:

• chr5-148063216-G-A
• chr5-148063216-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000521206.5(SPINK5):​c.-182-647G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 152,118 control chromosomes in the GnomAD database, including 43,573 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43573 hom., cov: 32)
• Consequence: SPINK5 ENST00000521206.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000521206.5	c.-182-647G>A		intron_variant		4		ENSP00000430264

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113301 AN: 152000 Hom.: 43520 Cov.: 32

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.854

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.737

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.746 AC: 113414 AN: 152118 Hom.: 43573 Cov.: 32 AF XY: 0.752 AC XY: 55937 AN XY: 74358

Gnomad4 AFR AF: 0.924

Gnomad4 AMR AF: 0.768

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.912

Gnomad4 SAS AF: 0.854

Gnomad4 FIN AF: 0.682

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.740

Alfa AF: 0.658 Hom.: 26314

Bravo AF: 0.760

Asia WGS AF: 0.884 AC: 3071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.28

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3756688; hg19: chr5-147442779; COSMIC: COSV56255528;