rs3736762

Variant names:

• chr20-34449531-C-T
• rs3736762
• NM_031483.7:c.1210+51C>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]

ENSG00000289720 (HGNC:):

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 rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.1210+51C>T		intron_variant	Intron 12 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.1210+51C>T		intron_variant	Intron 12 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.1210+51C>T		intron_variant	Intron 12 of 27			ENSP00000513014.1

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

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;