rs6059866

Positions:

• chr20-34488005-T-G

Variant summary

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

The NM_031483.7(ITCH):​c.2094-1261T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,998 control chromosomes in the GnomAD database, including 15,574 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 0.44 (15574 hom., cov: 32)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273

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=-0.92).
• 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	UniProt
ITCH	NM_031483.7	c.2094-1261T>G		intron_variant		ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10	c.2094-1261T>G		intron_variant		1	NM_031483.7	P1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67412 AN: 151880 Hom.: 15579 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.444 AC: 67418 AN: 151998 Hom.: 15574 Cov.: 32 AF XY: 0.447 AC XY: 33186 AN XY: 74304

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.593

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.456

Alfa AF: 0.451 Hom.: 3545

Bravo AF: 0.422

Asia WGS AF: 0.408 AC: 1421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.27

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: rs6059866; hg19: chr20-33075810;