chr20-34449416-A-G

Position:

• chr20-34449416-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_031483.7(ITCH):​c.1146A>G​(p.Gln382Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,606,038 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (43 hom.)
• Consequence: ITCH NM_031483.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.80

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]

ENSG00000289720 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 20-34449416-A-G is Benign according to our data. Variant chr20-34449416-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 471415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITCH	NM_031483.7	c.1146A>G	p.Gln382Gln	synonymous_variant	12/25	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.1146A>G	p.Gln382Gln	synonymous_variant	12/25	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.1146A>G		non_coding_transcript_exon_variant	12/28			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00834

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00583 AC: 1457 AN: 249982 Hom.: 7 AF XY: 0.00627 AC XY: 847 AN XY: 135052

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00849

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00728

Gnomad FIN exome AF: 0.00477

Gnomad NFE exome AF: 0.00796

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00696 AC: 10117 AN: 1453748 Hom.: 43 Cov.: 28 AF XY: 0.00704 AC XY: 5097 AN XY: 723620

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00910

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00782

Gnomad4 FIN exome AF: 0.00533

Gnomad4 NFE exome AF: 0.00759

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00529 AC: 806 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74460

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.00834

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00724 Hom.: 2

Bravo AF: 0.00475

Asia WGS AF: 0.00260 AC: 9 AN: 3474

EpiCase AF: 0.00895

EpiControl AF: 0.00897

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ITCH: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 11, 2021

- -

Syndromic multisystem autoimmune disease due to ITCH deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

ITCH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.0
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141828786; hg19: chr20-33037221; COSMIC: COSV52937799; COSMIC: COSV52937799;