Genetic Variant ITCH:c.966-9C>T (chr20-34445278-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_031483.7(ITCH):c.966-9C>T variant causes a 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 Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 0 hom., cov: 0)

Exomes 𝑓: 0.024 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

ITCH
NM_031483.7 intron

Scores

Splicing: ADA: 0.00002659

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.212

Publications

0 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 20-34445278-C-T is Benign according to our data. Variant chr20-34445278-C-T is described in ClinVar as [Benign]. Clinvar id is 471418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7 link	c.966-9C>T		intron_variant	Intron 10 of 24	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.966-9C>T		intron_variant	Intron 10 of 24	1	NM_031483.7	ENSP00000363998.4		Q96J02-2
ENSG00000289720	ENST00000696979.1 link	n.966-9C>T		intron_variant	Intron 10 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes

AF:

0.0348

AC:

1451

AN:

41698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.0470

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.0196

Gnomad SAS

AF:

0.0204

Gnomad FIN

AF:

0.0563

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0409

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.233

AC:

8319

AN:

35694

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.236

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.263

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0244

AC:

13978

AN:

571730

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

7677

AN XY:

285430

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0333

AC:

439

AN:

13178

American (AMR)

AF:

0.132

AC:

1678

AN:

12684

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

572

AN:

10018

East Asian (EAS)

AF:

0.0423

AC:

850

AN:

20098

South Asian (SAS)

AF:

0.0988

AC:

2352

AN:

23808

European-Finnish (FIN)

AF:

0.0755

AC:

1422

AN:

18822

Middle Eastern (MID)

AF:

0.0189

AC:

AN:

1798

European-Non Finnish (NFE)

AF:

0.0135

AC:

6035

AN:

446572

Other (OTH)

AF:

0.0241

AC:

596

AN:

24752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.291

Heterozygous variant carriers

1163

2325

3488

4650

5813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

216

324

432

540

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0348

AC:

1453

AN:

41736

Hom.:

Cov.:

AF XY:

0.0351

AC XY:

718

AN XY:

20434

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0293

AC:

338

AN:

11544

American (AMR)

AF:

0.0197

AC:

AN:

4626

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

AN:

852

East Asian (EAS)

AF:

0.0196

AC:

AN:

1634

South Asian (SAS)

AF:

0.0206

AC:

AN:

1502

European-Finnish (FIN)

AF:

0.0563

AC:

133

AN:

2362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0409

AC:

749

AN:

18316

Other (OTH)

AF:

0.0436

AC:

AN:

596

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

Heterozygous variant carriers

181

363

544

726

907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000833

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Syndromic multisystem autoimmune disease due to ITCH deficiency

Benign:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.3

(source)

DANN

Benign

0.73

PhyloP100

-0.21

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0020

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

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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