rs4357026

Variant names:

• chr5-148078376-G-C
• rs4357026
• NM_006846.4:c.282+6156G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-148078376-G-C
• chr5-148078376-G-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.282+6156G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 150,734 control chromosomes in the GnomAD database, including 43,223 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 0.75 (43223 hom., cov: 30)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• Publications: 2 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.282+6156G>C		intron	N/A	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.282+6156G>C		intron	N/A	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.282+6156G>C		intron	N/A	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.282+6156G>C		intron	N/A	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.282+6156G>C		intron	N/A	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.282+6156G>C		intron	N/A	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.746 AC: 112342 AN: 150618 Hom.: 43172 Cov.: 30

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.746 AC: 112452 AN: 150734 Hom.: 43223 Cov.: 30 AF XY: 0.753 AC XY: 55451 AN XY: 73650

African (AFR) AF: 0.923 AC: 38197 AN: 41370

American (AMR) AF: 0.771 AC: 11640 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2295 AN: 3446

East Asian (EAS) AF: 0.912 AC: 4650 AN: 5096

South Asian (SAS) AF: 0.854 AC: 4114 AN: 4816

European-Finnish (FIN) AF: 0.683 AC: 7173 AN: 10500

Middle Eastern (MID) AF: 0.702 AC: 205 AN: 292

European-Non Finnish (NFE) AF: 0.627 AC: 42116 AN: 67124

Other (OTH) AF: 0.740 AC: 1546 AN: 2090

Alfa AF: 0.559 Hom.: 1647

Bravo AF: 0.761

Asia WGS AF: 0.881 AC: 3027 AN: 3438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.97
DANN	Benign	0.42
PhyloP100		-0.19
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: rs4357026; hg19: chr5-147457939;