20-34470149-G-C

Variant names:

• chr20-34470149-G-C
• rs6059856
• NM_031483.7:c.1497+29G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031483.7(ITCH):​c.1497+29G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,545,090 control chromosomes in the GnomAD database, including 191,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (18400 hom., cov: 31)
  • Exomes 𝑓: 0.49 (173303 hom.)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.491
• Publications: 14 publications found

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]

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

ENSG00000289720 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-34470149-G-C is Benign according to our data. Variant chr20-34470149-G-C is described in ClinVar as Benign. ClinVar VariationId is 2628157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.1497+29G>C		intron_variant	Intron 15 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.1497+29G>C		intron_variant	Intron 15 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.1497+29G>C		intron_variant	Intron 15 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 74189 AN: 149080 Hom.: 18376 Cov.: 31

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.496

GnomAD2 exomes AF: 0.477 AC: 119834 AN: 251436 AF XY: 0.485

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.408

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.494 AC: 689318 AN: 1395888 Hom.: 173303 Cov.: 23 AF XY: 0.496 AC XY: 346134 AN XY: 698374

African (AFR) AF: 0.496 AC: 15942 AN: 32122

American (AMR) AF: 0.272 AC: 12155 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15592 AN: 25734

East Asian (EAS) AF: 0.365 AC: 14375 AN: 39368

South Asian (SAS) AF: 0.482 AC: 40891 AN: 84896

European-Finnish (FIN) AF: 0.584 AC: 31165 AN: 53384

Middle Eastern (MID) AF: 0.572 AC: 3227 AN: 5640

European-Non Finnish (NFE) AF: 0.501 AC: 526828 AN: 1051898

Other (OTH) AF: 0.501 AC: 29143 AN: 58212

GnomAD4 genome AF: 0.498 AC: 74252 AN: 149202 Hom.: 18400 Cov.: 31 AF XY: 0.501 AC XY: 36477 AN XY: 72844

African (AFR) AF: 0.496 AC: 20111 AN: 40506

American (AMR) AF: 0.381 AC: 5754 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2067 AN: 3458

East Asian (EAS) AF: 0.402 AC: 2047 AN: 5088

South Asian (SAS) AF: 0.492 AC: 2200 AN: 4470

European-Finnish (FIN) AF: 0.599 AC: 6207 AN: 10370

Middle Eastern (MID) AF: 0.514 AC: 150 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34294 AN: 66900

Other (OTH) AF: 0.498 AC: 1039 AN: 2086

Alfa AF: 0.523 Hom.: 3872

Bravo AF: 0.472

Asia WGS AF: 0.437 AC: 1521 AN: 3478

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	-0.85
CADD	Benign	7.4
DANN	Benign	0.61
PhyloP100		-0.49
Mutation Taster		=100/0	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: rs6059856; hg19: chr20-33057954; COSMIC: COSV52931469; COSMIC: COSV52931469;