rs60978485

Positions:

• chr5-148091116-A-T

Variant summary

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

The NM_006846.4(SPINK5):​c.603-49A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,515,472 control chromosomes in the GnomAD database, including 1,691 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 0.034 (147 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1544 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.364

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)

LOC124901185 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.603-49A>T		intron_variant		ENST00000256084.8
LOC124901185	XR_007059139.1	n.162-1313T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.603-49A>T		intron_variant		1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1418-1313T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5133 AN: 151806 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.00696

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0670

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.0450 AC: 10640 AN: 236476 Hom.: 364 AF XY: 0.0449 AC XY: 5762 AN XY: 128398

Gnomad AFR exome AF: 0.00435

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.0622

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0338

GnomAD4 exome AF: 0.0396 AC: 54040 AN: 1363548 Hom.: 1544 Cov.: 21 AF XY: 0.0402 AC XY: 27465 AN XY: 683868

Gnomad4 AFR exome AF: 0.00521

Gnomad4 AMR exome AF: 0.0535

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.0614

Gnomad4 FIN exome AF: 0.0529

Gnomad4 NFE exome AF: 0.0337

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0338 AC: 5139 AN: 151924 Hom.: 147 Cov.: 32 AF XY: 0.0367 AC XY: 2722 AN XY: 74260

Gnomad4 AFR AF: 0.00694

Gnomad4 AMR AF: 0.0540

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.0679

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0325 Hom.: 19

Bravo AF: 0.0311

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.66

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: rs60978485; hg19: chr5-147470679; COSMIC: COSV56265166;