5-148074074-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
SPINK5	NM_006846.4	c.282+1854T>G		intron_variant		ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.282+1854T>G		intron_variant		1	NM_006846.4	P2

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

Gnomad4 AFR AF: 0.757

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.787

Gnomad4 SAS AF: 0.786

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.595

Gnomad4 OTH AF: 0.688

Alfa AF: 0.623 Hom.: 13548

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4472254; hg19: chr5-147453637;