rs879012592

Variant names:

• chr20-34445278-C-A
• rs879012592
• NM_031483.7:c.966-9C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-34445278-C-A
• chr20-34445278-C-G
• chr20-34445278-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_031483.7(ITCH):​c.966-9C>A 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITCH NM_031483.7 intron
• Scores: Splicing: ADA: 0.0005665
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.212
• Publications: 0 publications found

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

ENSG00000289720 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-34445278-C-A is Benign according to our data. Variant chr20-34445278-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1114807.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.966-9C>A		intron_variant	Intron 10 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.966-9C>A		intron_variant	Intron 10 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.966-9C>A		intron_variant	Intron 10 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.000332 AC: 15 AN: 45120 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00469

Gnomad SAS AF: 0.000639

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000197

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0104 AC: 5980 AN: 577742 Hom.: 0 Cov.: 32 AF XY: 0.0101 AC XY: 2925 AN XY: 289080

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

African (AFR) AF: 0.00836 AC: 111 AN: 13282

American (AMR) AF: 0.00542 AC: 73 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.00994 AC: 102 AN: 10258

East Asian (EAS) AF: 0.00593 AC: 121 AN: 20396

South Asian (SAS) AF: 0.00341 AC: 88 AN: 25794

European-Finnish (FIN) AF: 0.00839 AC: 162 AN: 19298

Middle Eastern (MID) AF: 0.0146 AC: 27 AN: 1844

European-Non Finnish (NFE) AF: 0.0113 AC: 5049 AN: 448370

Other (OTH) AF: 0.00987 AC: 247 AN: 25028

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000332 AC: 15 AN: 45162 Hom.: 0 Cov.: 0 AF XY: 0.000413 AC XY: 9 AN XY: 21788

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

African (AFR) AF: 0.000162 AC: 2 AN: 12382

American (AMR) AF: 0.00 AC: 0 AN: 4816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 956

East Asian (EAS) AF: 0.00468 AC: 8 AN: 1710

South Asian (SAS) AF: 0.000644 AC: 1 AN: 1552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 74

European-Non Finnish (NFE) AF: 0.000197 AC: 4 AN: 20322

Other (OTH) AF: 0.00 AC: 0 AN: 642

⚠️ 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.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic multisystem autoimmune disease due to ITCH deficiency Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.63
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00057
dbscSNV1_RF	Benign	0.030
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

Other links and lift over

dbSNP: rs879012592; hg19: chr20-33033083;