ENST00000521206.5:c.-182-647G>A

Variant names:

• chr5-148063216-G-A
• rs3756688
• ENST00000521206.5:c.-182-647G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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]

SPINK5 Gene-Disease associations (from GenCC):

• Netherton syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000521206.5	c.-182-647G>A		intron_variant	Intron 1 of 4	4		ENSP00000430264.1

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

African (AFR) AF: 0.924 AC: 38356 AN: 41514

American (AMR) AF: 0.768 AC: 11742 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2332 AN: 3472

East Asian (EAS) AF: 0.912 AC: 4710 AN: 5162

South Asian (SAS) AF: 0.854 AC: 4116 AN: 4820

European-Finnish (FIN) AF: 0.682 AC: 7212 AN: 10568

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42660 AN: 67976

Other (OTH) AF: 0.740 AC: 1562 AN: 2112

Alfa AF: 0.673 Hom.: 35835

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
PhyloP100		0.22

Splicing

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

Other links and lift over

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