Variant rs141828786 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_031483.7(ITCH):c.1146A>G(p.Gln382=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,606,038 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 43 hom. )

Consequence

ITCH
NM_031483.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.80

Variant links:

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]

ITCH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 20-34449416-A-G is Benign according to our data. Variant chr20-34449416-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 471415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.8 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITCH	NM_031483.7 linkuse as main transcript	c.1146A>G	p.Gln382=	synonymous_variant	12/25	ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10 linkuse as main transcript	c.1146A>G	p.Gln382=	synonymous_variant	12/25	1	NM_031483.7	P1	Q96J02-2

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00834

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00583

AC:

1457

AN:

249982

Hom.:

AF XY:

0.00627

AC XY:

847

AN XY:

135052

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00849

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00728

Gnomad FIN exome

AF:

0.00477

Gnomad NFE exome

AF:

0.00796

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00696

AC:

10117

AN:

1453748

Hom.:

Cov.:

AF XY:

0.00704

AC XY:

5097

AN XY:

723620

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00910

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00782

Gnomad4 FIN exome

AF:

0.00533

Gnomad4 NFE exome

AF:

0.00759

Gnomad4 OTH exome

AF:

0.00596

GnomAD4 genome

AF:

0.00529

AC:

806

AN:

152290

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.00834

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00724

Hom.:

Bravo

AF:

0.00475

Asia WGS

AF:

0.00260

AC:

AN:

3474

EpiCase

AF:

0.00895

EpiControl

AF:

0.00897

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 11, 2021

- -

Syndromic multisystem autoimmune disease due to ITCH deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

ITCH-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

ITCH: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.0

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over