rs879012592

chr20-34445278-C-Achr20-34445278-C-Gchr20-34445278-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_031483.7(ITCH):c.966-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITCH NM_031483.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005665
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.212

Genes affected

ITCH (HGNC:13890): (itchy E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-34445278-C-A is Benign according to our data. Variant chr20-34445278-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1114807.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-34445278-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITCH	NM_031483.7	c.966-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10	c.966-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_031483.7	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 15 AN: 45120 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00469

Gnomad SAS AF: 0.000639

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000197

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0104 AC: 5980 AN: 577742 Hom.: 0 Cov.: 32 AF XY: 0.0101 AC XY: 2925 AN XY: 289080

Gnomad4 AFR exome AF: 0.00836

Gnomad4 AMR exome AF: 0.00542

Gnomad4 ASJ exome AF: 0.00994

Gnomad4 EAS exome AF: 0.00593

Gnomad4 SAS exome AF: 0.00341

Gnomad4 FIN exome AF: 0.00839

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00987

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000332 AC: 15 AN: 45162 Hom.: 0 Cov.: 0 AF XY: 0.000413 AC XY: 9 AN XY: 21788

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00468

Gnomad4 SAS AF: 0.000644

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000197

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic multisystem autoimmune disease due to ITCH deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.4
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00057
dbscSNV1_RF	Benign	0.030
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: rs879012592; hg19: chr20-33033083;