rs3746455

chr20-34369410-G-Achr20-34369410-G-Cchr20-34369410-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_031483.7(ITCH):c.-82G>A variant causes a 5 prime UTR 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: ITCH NM_031483.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
ITCH	NM_031483.7	c.-82G>A		5_prime_UTR_variant	2/25	ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10	c.-82G>A		5_prime_UTR_variant	2/25	1	NM_031483.7	P1

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

Gnomad4 AFR exome AF: 0.668

Gnomad4 AMR exome AF: 0.685

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.656

Gnomad4 SAS exome AF: 0.550

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.606

Gnomad4 SAS AF: 0.571

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.546

Alfa AF: 0.501 Hom.: 31691

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
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs3746455; hg19: chr20-32957216;