chr20-34424254-C-T

Position:

• chr20-34424254-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000374864.10(ITCH):​c.476-226C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,908 control chromosomes in the GnomAD database, including 15,783 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 0.45 (15783 hom., cov: 32)
• Consequence: ITCH ENST00000374864.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITCH	NM_031483.7	c.476-226C>T		intron_variant		ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.476-226C>T		intron_variant		1	NM_031483.7	ENSP00000363998	P1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67976 AN: 151790 Hom.: 15776 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.457

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.448 AC: 68016 AN: 151908 Hom.: 15783 Cov.: 32 AF XY: 0.451 AC XY: 33472 AN XY: 74244

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.460

Alfa AF: 0.429 Hom.: 4138

Bravo AF: 0.426

Asia WGS AF: 0.413 AC: 1437 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.0
DANN	Benign	0.72

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: rs2424992; hg19: chr20-33012060;