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

Variant summary

Our verdict is Benign. Variant got -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

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:

ENSG00000289720 (HGNC:):

ENSG00000289720 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr20-34445278-C-T is described in Lovd as [Likely_benign].

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:

0.00

AC:

1451

AN:

41698

Hom.:

Cov.:

FAILED QC

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

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

Gnomad4 AFR exome

AF:

0.0333

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.0571

Gnomad4 EAS exome

AF:

0.0423

Gnomad4 SAS exome

AF:

0.0988

Gnomad4 FIN exome

AF:

0.0755

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0241

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

Gnomad4 AFR

AF:

0.0293

Gnomad4 AMR

AF:

0.0197

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.0196

Gnomad4 SAS

AF:

0.0206

Gnomad4 FIN

AF:

0.0563

Gnomad4 NFE

AF:

0.0409

Gnomad4 OTH

AF:

0.0436

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

DANN

Benign

0.73

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

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