NM_031483.7:c.966-7G>T

Variant names:

• chr20-34445280-G-T
• rs773671382
• NM_031483.7:c.966-7G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_031483.7(ITCH):​c.966-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.0015 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITCH NM_031483.7 splice_region, intron
• Scores: Splicing: ADA: 0.00001559
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0230

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]

ENSG00000289720 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-34445280-G-T is Benign according to our data. Variant chr20-34445280-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 471417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-34445280-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.966-7G>T		splice_region_variant, intron_variant	Intron 10 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.966-7G>T		splice_region_variant, intron_variant	Intron 10 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.966-7G>T		splice_region_variant, intron_variant	Intron 10 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 126 AN: 82942 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00187

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00156

Gnomad EAS AF: 0.000940

Gnomad SAS AF: 0.00173

Gnomad FIN AF: 0.00722

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.000877

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00196 AC: 1679 AN: 855588 Hom.: 0 Cov.: 35 AF XY: 0.00203 AC XY: 878 AN XY: 433022

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00923

Gnomad4 ASJ exome AF: 0.00527

Gnomad4 EAS exome AF: 0.00137

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.00545

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00152 AC: 126 AN: 82976 Hom.: 0 Cov.: 25 AF XY: 0.00167 AC XY: 66 AN XY: 39408

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00106

Gnomad4 ASJ AF: 0.00156

Gnomad4 EAS AF: 0.000939

Gnomad4 SAS AF: 0.00174

Gnomad4 FIN AF: 0.00722

Gnomad4 NFE AF: 0.00130

Gnomad4 OTH AF: 0.000871

Alfa AF: 0.000672 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic multisystem autoimmune disease due to ITCH deficiency Benign:3

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs773671382; hg19: chr20-33033085;