rs190365795

Variant names:

• chr5-148118980-C-T
• rs190365795
• NM_006846.4:c.2241-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.2241-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,613,660 control chromosomes in the GnomAD database, including 98 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 0.0079 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (83 hom.)
• Consequence: SPINK5 NM_006846.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002109
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0850
• Publications: 2 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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-148118980-C-T is Benign according to our data. Variant chr5-148118980-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00789 (1201/152260) while in subpopulation NFE AF = 0.00864 (588/68028). AF 95% confidence interval is 0.00807. There are 15 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2241-6C>T		splice_region intron	N/A	NP_006837.2
	SPINK5	NM_001127698.2		c.2241-6C>T		splice_region intron	N/A	NP_001121170.1
	SPINK5	NM_001127699.2		c.2241-6C>T		splice_region intron	N/A	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2241-6C>T		splice_region intron	N/A	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.2241-6C>T		splice_region intron	N/A	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.2241-6C>T		splice_region intron	N/A	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152142 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00864

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00810 AC: 2020 AN: 249300 AF XY: 0.00764

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.00829

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00726 AC: 10615 AN: 1461400 Hom.: 83 Cov.: 34 AF XY: 0.00714 AC XY: 5193 AN XY: 727026

African (AFR) AF: 0.000866 AC: 29 AN: 33474

American (AMR) AF: 0.00119 AC: 53 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86228

European-Finnish (FIN) AF: 0.0411 AC: 2192 AN: 53344

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00697 AC: 7744 AN: 1111696

Other (OTH) AF: 0.00644 AC: 389 AN: 60376

GnomAD4 genome AF: 0.00789 AC: 1201 AN: 152260 Hom.: 15 Cov.: 33 AF XY: 0.00865 AC XY: 644 AN XY: 74432

African (AFR) AF: 0.00123 AC: 51 AN: 41538

American (AMR) AF: 0.00288 AC: 44 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0435 AC: 461 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00864 AC: 588 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00852 Hom.: 7

Bravo AF: 0.00450

EpiCase AF: 0.00785

EpiControl AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.38
PhyloP100		0.085
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs190365795; hg19: chr5-147498543;