rs1422993

Positions:

• chr5-148124257-A-C
• chr5-148124257-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006846.4(SPINK5):​c.2666+297A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,136 control chromosomes in the GnomAD database, including 47,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.79 (47027 hom., cov: 32)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.35

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]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-148124257-A-C is Benign according to our data. Variant chr5-148124257-A-C is described in ClinVar as [Benign]. Clinvar id is 667633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.2666+297A>C		intron_variant		ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.2666+297A>C		intron_variant		1	NM_006846.4	P2
SPINK5	ENST00000359874.7	c.2666+297A>C		intron_variant		1		A2
SPINK5	ENST00000398454.5	c.2666+297A>C		intron_variant		1
FBXO38-DT	ENST00000667608.1	n.1257-30515T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119466 AN: 152018 Hom.: 46988 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.774

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

GnomAD4 genome AF: 0.786 AC: 119564 AN: 152136 Hom.: 47027 Cov.: 32 AF XY: 0.790 AC XY: 58718 AN XY: 74350

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.813

Gnomad4 ASJ AF: 0.752

Gnomad4 EAS AF: 0.915

Gnomad4 SAS AF: 0.873

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.754

Gnomad4 OTH AF: 0.775

Alfa AF: 0.765 Hom.: 43726

Bravo AF: 0.788

Asia WGS AF: 0.883 AC: 3056 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.37

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: rs1422993; hg19: chr5-147503820;