chr20-34369410-G-A

Variant names:

• chr20-34369410-G-A
• rs3746455
• ENST00000696979.1:n.-82G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000696979.1(ENSG00000289720):​n.-82G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 398,614 control chromosomes in the GnomAD database, including 57,461 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 0.56 (24251 hom., cov: 32)
  • Exomes 𝑓: 0.51 (33210 hom.)
• Consequence: ENSG00000289720 ENST00000696979.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• Publications: 20 publications found

Genes affected

ENSG00000289720 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.-82G>A		5_prime_UTR_variant	Exon 2 of 25	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289720	ENST00000696979.1	n.-82G>A		non_coding_transcript_exon_variant	Exon 2 of 28			ENSP00000513014.1
ITCH	ENST00000374864.10	c.-82G>A		5_prime_UTR_variant	Exon 2 of 25	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.-82G>A		5_prime_UTR_variant	Exon 2 of 28			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84620 AN: 151836 Hom.: 24200 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.549

GnomAD4 exome AF: 0.513 AC: 126544 AN: 246660 Hom.: 33210 Cov.: 0 AF XY: 0.511 AC XY: 63891 AN XY: 125026

African (AFR) AF: 0.668 AC: 4796 AN: 7176

American (AMR) AF: 0.685 AC: 5094 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 3663 AN: 9242

East Asian (EAS) AF: 0.656 AC: 15008 AN: 22888

South Asian (SAS) AF: 0.550 AC: 1668 AN: 3030

European-Finnish (FIN) AF: 0.417 AC: 8852 AN: 21238

Middle Eastern (MID) AF: 0.459 AC: 594 AN: 1294

European-Non Finnish (NFE) AF: 0.496 AC: 78430 AN: 157988

Other (OTH) AF: 0.515 AC: 8439 AN: 16372

GnomAD4 genome AF: 0.558 AC: 84737 AN: 151954 Hom.: 24251 Cov.: 32 AF XY: 0.555 AC XY: 41201 AN XY: 74272

African (AFR) AF: 0.665 AC: 27538 AN: 41430

American (AMR) AF: 0.642 AC: 9802 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3468

East Asian (EAS) AF: 0.606 AC: 3132 AN: 5166

South Asian (SAS) AF: 0.571 AC: 2746 AN: 4810

European-Finnish (FIN) AF: 0.409 AC: 4315 AN: 10558

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33958 AN: 67948

Other (OTH) AF: 0.546 AC: 1154 AN: 2112

Alfa AF: 0.519 Hom.: 57364

Bravo AF: 0.579

Asia WGS AF: 0.590 AC: 2051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3746455; hg19: chr20-32957216;