5-148064026-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):c.-19G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0086 in 1,614,022 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (77 hom.)
• Consequence: SPINK5 NM_006846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-148064026-G-A is Benign according to our data. Variant chr5-148064026-G-A is described in ClinVar as [Benign]. Clinvar id is 904043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148064026-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00639 (973/152252) while in subpopulation NFE AF= 0.01 (683/68018). AF 95% confidence interval is 0.00942. There are 6 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.-19G>A		5_prime_UTR_variant	1/33	ENST00000256084.8
SPINK5	NM_001127698.2	c.-19G>A		5_prime_UTR_variant	1/34
SPINK5	NM_001127699.2	c.-19G>A		5_prime_UTR_variant	1/28
SPINK5	XM_047416662.1	c.-19G>A		5_prime_UTR_variant	1/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.-19G>A		5_prime_UTR_variant	1/33	1	NM_006846.4	P2

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 973 AN: 152134 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00834 AC: 2082 AN: 249534 Hom.: 19 AF XY: 0.00830 AC XY: 1124 AN XY: 135378

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00907

GnomAD4 exome AF: 0.00883 AC: 12909 AN: 1461770 Hom.: 77 Cov.: 30 AF XY: 0.00882 AC XY: 6414 AN XY: 727190

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00993

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00406

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00980

Gnomad4 OTH exome AF: 0.00785

GnomAD4 genome AF: 0.00639 AC: 973 AN: 152252 Hom.: 6 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74452

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00839

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00881 Hom.: 3

Bravo AF: 0.00608

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Netherton syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.16
Dann	Benign	0.87

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: rs12522603; hg19: chr5-147443589;