5-148074074-T-G

Variant names:

• chr5-148074074-T-G
• rs4472254
• NM_006846.4:c.282+1854T>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.282+1854T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,474 control chromosomes in the GnomAD database, including 34,157 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 0.67 (34157 hom., cov: 30)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.905
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.282+1854T>G		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.282+1854T>G		intron_variant	Intron 4 of 32	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.667 AC: 100896 AN: 151358 Hom.: 34141 Cov.: 30

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.707

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.685

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

GnomAD4 genome AF: 0.667 AC: 100961 AN: 151474 Hom.: 34157 Cov.: 30 AF XY: 0.672 AC XY: 49705 AN XY: 73980

African (AFR) AF: 0.757 AC: 31314 AN: 41368

American (AMR) AF: 0.703 AC: 10650 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2186 AN: 3458

East Asian (EAS) AF: 0.787 AC: 4002 AN: 5088

South Asian (SAS) AF: 0.786 AC: 3781 AN: 4812

European-Finnish (FIN) AF: 0.625 AC: 6590 AN: 10550

Middle Eastern (MID) AF: 0.699 AC: 204 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 40280 AN: 67740

Other (OTH) AF: 0.688 AC: 1451 AN: 2110

Alfa AF: 0.620 Hom.: 14935

Bravo AF: 0.679

Asia WGS AF: 0.786 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.61
PhyloP100		0.91
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: rs4472254; hg19: chr5-147453637;