rs185217593

Variant names:

• chr5-148091162-C-T
• rs185217593
• NM_006846.4:c.603-3C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006846.4(SPINK5):​c.603-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000652 in 1,610,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SPINK5 NM_006846.4 splice_region, intron
• Scores: Splicing: ADA: 0.004535
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691
• Publications: 0 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)

LOC124901185 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.603-3C>T		splice_region intron	N/A	NP_006837.2
	SPINK5	NM_001127698.2		c.603-3C>T		splice_region intron	N/A	NP_001121170.1
	SPINK5	NM_001127699.2		c.603-3C>T		splice_region intron	N/A	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.603-3C>T		splice_region intron	N/A	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.603-3C>T		splice_region intron	N/A	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.603-3C>T		splice_region intron	N/A	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 49 AN: 151736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000810 AC: 20 AN: 246976 AF XY: 0.0000672

Gnomad AFR exome AF: 0.000780

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000377 AC: 55 AN: 1458652 Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23 AN XY: 725696

African (AFR) AF: 0.00126 AC: 42 AN: 33314

American (AMR) AF: 0.000180 AC: 8 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110208

Other (OTH) AF: 0.0000498 AC: 3 AN: 60192

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151854 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74208

African (AFR) AF: 0.00116 AC: 48 AN: 41478

American (AMR) AF: 0.000131 AC: 2 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67860

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000302

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Netherton syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0045
dbscSNV1_RF	Benign	0.084
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: rs185217593; hg19: chr5-147470725;