rs3736762

chr20-34449531-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031483.7(ITCH):c.1210+51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,193,640 control chromosomes in the GnomAD database, including 143,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15737 hom., cov: 31)
  • Exomes 𝑓: 0.49 (127295 hom.)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-34449531-C-T is Benign according to our data. Variant chr20-34449531-C-T is described in ClinVar as [Benign]. Clinvar id is 2628156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITCH	NM_031483.7	c.1210+51C>T		intron_variant		ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10	c.1210+51C>T		intron_variant		1	NM_031483.7	P1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67888 AN: 151720 Hom.: 15730 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.457

GnomAD3 exomes AF: 0.458 AC: 109681 AN: 239352 Hom.: 26412 AF XY: 0.468 AC XY: 60409 AN XY: 129050

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.407

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.488 AC: 507880 AN: 1041802 Hom.: 127295 Cov.: 14 AF XY: 0.489 AC XY: 261955 AN XY: 535980

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.584

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.490

GnomAD4 genome AF: 0.447 AC: 67928 AN: 151838 Hom.: 15737 Cov.: 31 AF XY: 0.450 AC XY: 33408 AN XY: 74186

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.460

Alfa AF: 0.468 Hom.: 4469

Bravo AF: 0.426

Asia WGS AF: 0.414 AC: 1440 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.81
Dann	Benign	0.49

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: rs3736762; hg19: chr20-33037336; COSMIC: COSV52932237; COSMIC: COSV52932237;