Genetic Variant ITCH:c.476-226C>T (chr20-34424254-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031483.7(ITCH):c.476-226C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,908 control chromosomes in the GnomAD database, including 15,783 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 15783 hom., cov: 32)

Consequence

ITCH
NM_031483.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.236

Publications

6 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=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7 link	c.476-226C>T		intron_variant	Intron 6 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.476-226C>T		intron_variant	Intron 6 of 24	1	NM_031483.7	ENSP00000363998.4		Q96J02-2
ENSG00000289720	ENST00000696979.1 link	n.476-226C>T		intron_variant	Intron 6 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

67976

AN:

151790

Hom.:

15776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.591

Gnomad EAS

AF:

0.396

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.510

Gnomad NFE

AF:

0.501

Gnomad OTH

AF:

0.457

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.448

AC:

68016

AN:

151908

Hom.:

15783

Cov.:

AF XY:

0.451

AC XY:

33472

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.352

AC:

14582

AN:

41430

American (AMR)

AF:

0.361

AC:

5512

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

2052

AN:

3470

East Asian (EAS)

AF:

0.395

AC:

2037

AN:

5154

South Asian (SAS)

AF:

0.426

AC:

2050

AN:

4812

European-Finnish (FIN)

AF:

0.592

AC:

6241

AN:

10548

Middle Eastern (MID)

AF:

0.507

AC:

147

AN:

290

European-Non Finnish (NFE)

AF:

0.501

AC:

34043

AN:

67934

Other (OTH)

AF:

0.460

AC:

971

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1905

3810

5716

7621

9526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.425

Hom.:

4575

Bravo

AF:

0.426

Asia WGS

AF:

0.413

AC:

1437

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

3.0

(source)

DANN

Benign

0.72

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over