NM_006846.4:c.283-716C>T

Variant names:

• chr5-148085689-C-T
• rs7724165
• NM_006846.4:c.283-716C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006846.4(SPINK5):​c.283-716C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,534 control chromosomes in the GnomAD database, including 17,096 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 0.46 (17096 hom., cov: 31)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 1 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

LOC124901185 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.283-716C>T		intron_variant	Intron 4 of 32	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.283-716C>T		intron_variant	Intron 4 of 32	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70374 AN: 151420 Hom.: 17093 Cov.: 31

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.464 AC: 70384 AN: 151534 Hom.: 17096 Cov.: 31 AF XY: 0.470 AC XY: 34768 AN XY: 74040

African (AFR) AF: 0.307 AC: 12697 AN: 41332

American (AMR) AF: 0.594 AC: 9019 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1707 AN: 3462

East Asian (EAS) AF: 0.494 AC: 2512 AN: 5082

South Asian (SAS) AF: 0.495 AC: 2386 AN: 4822

European-Finnish (FIN) AF: 0.534 AC: 5638 AN: 10566

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34768 AN: 67778

Other (OTH) AF: 0.497 AC: 1044 AN: 2100

Alfa AF: 0.496 Hom.: 9644

Bravo AF: 0.465

Asia WGS AF: 0.529 AC: 1833 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	6.3
DANN	Benign	0.37
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7724165; hg19: chr5-147465252;