rs1422985

Positions:

• chr5-148114596-A-C

Variant summary

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

The ENST00000256084.8(SPINK5):​c.2015+107A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,498,276 control chromosomes in the GnomAD database, including 1,651 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 0.033 (147 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1504 hom.)
• Consequence: SPINK5 ENST00000256084.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2015+107A>C		intron_variant		ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.2015+107A>C		intron_variant		1	NM_006846.4	ENSP00000256084	P2
FBXO38-DT	ENST00000667608.1	n.1257-20854T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5082 AN: 152168 Hom.: 147 Cov.: 33

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0395 AC: 53172 AN: 1345990 Hom.: 1504 AF XY: 0.0400 AC XY: 26971 AN XY: 673686

Gnomad4 AFR exome AF: 0.00500

Gnomad4 AMR exome AF: 0.0536

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.0606

Gnomad4 FIN exome AF: 0.0529

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0369

GnomAD4 genome AF: 0.0334 AC: 5086 AN: 152286 Hom.: 147 Cov.: 33 AF XY: 0.0360 AC XY: 2682 AN XY: 74472

Gnomad4 AFR AF: 0.00702

Gnomad4 AMR AF: 0.0545

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0624

Gnomad4 FIN AF: 0.0575

Gnomad4 NFE AF: 0.0334

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0345 Hom.: 15

Bravo AF: 0.0308

Asia WGS AF: 0.0820 AC: 286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.61

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: rs1422985; hg19: chr5-147494159; COSMIC: COSV56265206;