dbSNP rs1297985937: ITCH:c.213-8A>T (chr20-34412507-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001257137.3(ITCH):c.213-8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITCH
NM_001257137.3 splice_region, intron

Scores

Splicing: ADA: 0.00002180

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0750

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 20-34412507-A-T is Benign according to our data. Variant chr20-34412507-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538755.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257137.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITCH	NM_031483.7	MANE Select	c.213-8A>T	splice_region intron	N/A	NP_113671.3
ITCH	NM_001257137.3		c.213-8A>T	splice_region intron	N/A	NP_001244066.1
ITCH	NM_001324197.2		c.213-8A>T	splice_region intron	N/A	NP_001311126.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITCH	ENST00000374864.10	TSL:1 MANE Select	c.213-8A>T	splice_region intron	N/A	ENSP00000363998.4
ITCH	ENST00000262650.11	TSL:1	c.213-8A>T	splice_region intron	N/A	ENSP00000262650.5
ENSG00000289720	ENST00000696979.1		n.213-8A>T	splice_region intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151920

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

249706

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1422868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710108

African (AFR)

AF:

0.00

AC:

AN:

32568

American (AMR)

AF:

0.00

AC:

AN:

44288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25830

East Asian (EAS)

AF:

0.00

AC:

AN:

39386

South Asian (SAS)

AF:

0.00

AC:

AN:

85180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077564

Other (OTH)

AF:

0.00

AC:

AN:

59068

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74190

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2086

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Syndromic multisystem autoimmune disease due to ITCH deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.5

(source)

DANN

Benign

0.54

PhyloP100

0.075

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over