rs180955184

chr5-148124761-G-Achr5-148124761-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006846.4(SPINK5):c.2667-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,583,566 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (44 hom.)
• Consequence: SPINK5 NM_006846.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004642
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.364

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-148124761-G-A is Benign according to our data. Variant chr5-148124761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148124761-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.2667-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.2667-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006846.4	P2
SPINK5	ENST00000359874.7	c.2667-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2
SPINK5	ENST00000398454.5	c.2667-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
FBXO38-DT	ENST00000667608.1	n.1257-31019C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 759 AN: 148384 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000372

Gnomad AMI AF: 0.00991

Gnomad AMR AF: 0.000473

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00212

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00343

GnomAD3 exomes AF: 0.00567 AC: 1309 AN: 231018 Hom.: 13 AF XY: 0.00573 AC XY: 717 AN XY: 125214

Gnomad AFR exome AF: 0.000359

Gnomad AMR exome AF: 0.000400

Gnomad ASJ exome AF: 0.000528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00416 AC: 5977 AN: 1435076 Hom.: 44 Cov.: 30 AF XY: 0.00415 AC XY: 2963 AN XY: 713384

Gnomad4 AFR exome AF: 0.000430

Gnomad4 AMR exome AF: 0.000354

Gnomad4 ASJ exome AF: 0.000866

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00511 AC: 759 AN: 148490 Hom.: 17 Cov.: 32 AF XY: 0.00677 AC XY: 488 AN XY: 72112

Gnomad4 AFR AF: 0.000370

Gnomad4 AMR AF: 0.000472

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00212

Gnomad4 FIN AF: 0.0454

Gnomad4 NFE AF: 0.00420

Gnomad4 OTH AF: 0.00339

Alfa AF: 0.00300 Hom.: 3

Bravo AF: 0.00194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Netherton syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.1
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs180955184; hg19: chr5-147504324;