rs141828786

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_031483.7(ITCH):c.1146A>G(p.Gln382Gln) 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:5

Conservation

PhyloP100: 1.80

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

syndromic multisystem autoimmune disease due to ITCH deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ITCH links:

ENSG00000289720 (HGNC:):

ENSG00000289720 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
ITCH	NM_031483.7 link	c.1146A>G	p.Gln382Gln	synonymous_variant	Exon 12 of 25	ENST00000374864.10	NP_113671.3	Q96J02-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10 link	c.1146A>G	p.Gln382Gln	synonymous_variant	Exon 12 of 25	1	NM_031483.7	ENSP00000363998.4		Q96J02-2
ENSG00000289720	ENST00000696979.1 link	n.1146A>G		non_coding_transcript_exon_variant	Exon 12 of 28			ENSP00000513014.1

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

GnomAD2 exomes

AF:

0.00583

AC:

1457

AN:

249982

AF XY:

0.00627

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 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

African (AFR)

AF:

0.00108

AC:

AN:

33326

American (AMR)

AF:

0.00264

AC:

118

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00910

AC:

237

AN:

26036

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39594

South Asian (SAS)

AF:

0.00782

AC:

672

AN:

85918

European-Finnish (FIN)

AF:

0.00533

AC:

284

AN:

53318

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00759

AC:

8384

AN:

1105112

Other (OTH)

AF:

0.00596

AC:

358

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

420

840

1260

1680

2100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00529

AC:

806

AN:

152290

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41566

American (AMR)

AF:

0.00321

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00808

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00834

AC:

567

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITCH: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jun 11, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndromic multisystem autoimmune disease due to ITCH deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ITCH-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.0

(source)

DANN

Benign

0.88

PhyloP100

1.8

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over