chr20-34445280-G-T

Variant names:

• chr20-34445280-G-T
• rs773671382
• NM_031483.7:c.966-7G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_031483.7(ITCH):​c.966-7G>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 0.0015 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITCH NM_031483.7 splice_region, intron
• Scores: Splicing: ADA: 0.00001559
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0230
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-34445280-G-T is Benign according to our data. Variant chr20-34445280-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 471417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	NM_031483.7	MANE Select	c.966-7G>T		splice_region intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.1089-7G>T		splice_region intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.1089-7G>T		splice_region intron	N/A	NP_001311126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.966-7G>T		splice_region intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.1089-7G>T		splice_region intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.966-7G>T		splice_region intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 126 AN: 82942 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00187

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00156

Gnomad EAS AF: 0.000940

Gnomad SAS AF: 0.00173

Gnomad FIN AF: 0.00722

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.000877

GnomAD2 exomes AF: 0.0106 AC: 1668 AN: 158096 AF XY: 0.0102

Gnomad AFR exome AF: 0.00475

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.0130

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.0139

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00196 AC: 1679 AN: 855588 Hom.: 0 Cov.: 35 AF XY: 0.00203 AC XY: 878 AN XY: 433022

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

African (AFR) AF: 0.00323 AC: 62 AN: 19174

American (AMR) AF: 0.00923 AC: 228 AN: 24702

Ashkenazi Jewish (ASJ) AF: 0.00527 AC: 83 AN: 15740

East Asian (EAS) AF: 0.00137 AC: 37 AN: 27074

South Asian (SAS) AF: 0.00546 AC: 265 AN: 48524

European-Finnish (FIN) AF: 0.00545 AC: 188 AN: 34520

Middle Eastern (MID) AF: 0.00426 AC: 13 AN: 3052

European-Non Finnish (NFE) AF: 0.00115 AC: 744 AN: 646310

Other (OTH) AF: 0.00162 AC: 59 AN: 36492

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00152 AC: 126 AN: 82976 Hom.: 0 Cov.: 25 AF XY: 0.00167 AC XY: 66 AN XY: 39408

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

African (AFR) AF: 0.00131 AC: 30 AN: 22960

American (AMR) AF: 0.00106 AC: 9 AN: 8512

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 3 AN: 1918

East Asian (EAS) AF: 0.000939 AC: 3 AN: 3194

South Asian (SAS) AF: 0.00174 AC: 5 AN: 2872

European-Finnish (FIN) AF: 0.00722 AC: 24 AN: 3322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00130 AC: 50 AN: 38374

Other (OTH) AF: 0.000871 AC: 1 AN: 1148

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000672 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic multisystem autoimmune disease due to ITCH deficiency Benign:3

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 18, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		0.023
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs773671382; hg19: chr20-33033085;