dbSNP rs6120644: ITCH:c.522-2469G>A (chr20-34436005-G-A) – 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.522-2469G>A 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 151,896 control chromosomes in the GnomAD database, including 15,766 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 ( 15766 hom., cov: 31)

Consequence

ITCH
NM_031483.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0810

Publications

7 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

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=-0.95).

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031483.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ITCH	NM_031483.7	MANE Select	c.522-2469G>A	intron	N/A	NP_113671.3
ITCH	NM_001257137.3		c.645-2469G>A	intron	N/A	NP_001244066.1	Q96J02-1
ITCH	NM_001324197.2		c.645-2469G>A	intron	N/A	NP_001311126.1	Q96J02-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ITCH	ENST00000374864.10	TSL:1 MANE Select	c.522-2469G>A	intron	N/A	ENSP00000363998.4	Q96J02-2
ITCH	ENST00000262650.11	TSL:1	c.645-2469G>A	intron	N/A	ENSP00000262650.5	Q96J02-1
ENSG00000289720	ENST00000696979.1		n.522-2469G>A	intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

67953

AN:

151778

Hom.:

15759

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:

0.394

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.501

Gnomad OTH

AF:

0.456

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

GnomAD4 genome

AF:

0.448

AC:

67991

AN:

151896

Hom.:

15766

Cov.:

AF XY:

0.451

AC XY:

33444

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.352

AC:

14583

AN:

41412

American (AMR)

AF:

0.361

AC:

5514

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

2051

AN:

3468

East Asian (EAS)

AF:

0.393

AC:

2024

AN:

5154

South Asian (SAS)

AF:

0.426

AC:

2052

AN:

4818

European-Finnish (FIN)

AF:

0.592

AC:

6239

AN:

10540

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.501

AC:

34033

AN:

67928

Other (OTH)

AF:

0.459

AC:

968

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1878

3756

5634

7512

9390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.453

Hom.:

5302

Bravo

AF:

0.427

Asia WGS

AF:

0.412

AC:

1433

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.0

(source)

DANN

Benign

0.39

PhyloP100

-0.081

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over