NM_006846.4:c.210-139A>G

Variant names:

• chr5-148072009-A-G
• rs17718511
• NM_006846.4:c.210-139A>G

Variant summary

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

The NM_006846.4(SPINK5):​c.210-139A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 733,196 control chromosomes in the GnomAD database, including 1,108 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 (148 hom., cov: 32)
  • Exomes 𝑓: 0.045 (960 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.424
• Publications: 5 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=-0.82).
• 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 rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.210-139A>G		intron_variant	Intron 3 of 32	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.210-139A>G		intron_variant	Intron 3 of 32	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5134 AN: 152004 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0452 AC: 26245 AN: 581074 Hom.: 960 AF XY: 0.0455 AC XY: 14180 AN XY: 311930

African (AFR) AF: 0.00626 AC: 100 AN: 15962

American (AMR) AF: 0.0534 AC: 1783 AN: 33402

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 561 AN: 18786

East Asian (EAS) AF: 0.165 AC: 5083 AN: 30824

South Asian (SAS) AF: 0.0615 AC: 3852 AN: 62590

European-Finnish (FIN) AF: 0.0527 AC: 2434 AN: 46212

Middle Eastern (MID) AF: 0.00733 AC: 28 AN: 3822

European-Non Finnish (NFE) AF: 0.0335 AC: 11372 AN: 339642

Other (OTH) AF: 0.0346 AC: 1032 AN: 29834

GnomAD4 genome AF: 0.0338 AC: 5140 AN: 152122 Hom.: 148 Cov.: 32 AF XY: 0.0366 AC XY: 2725 AN XY: 74362

African (AFR) AF: 0.00700 AC: 291 AN: 41552

American (AMR) AF: 0.0538 AC: 820 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3466

East Asian (EAS) AF: 0.125 AC: 644 AN: 5144

South Asian (SAS) AF: 0.0677 AC: 327 AN: 4828

European-Finnish (FIN) AF: 0.0573 AC: 607 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2277 AN: 67978

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0324 Hom.: 17

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	-0.82
CADD	Benign	3.0
DANN	Benign	0.58
PhyloP100		0.42
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: rs17718511; hg19: chr5-147451572; COSMIC: COSV107188353;