20-34424254-C-T

Variant names:

• chr20-34424254-C-T
• rs2424992
• NM_031483.7:c.476-226C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031483.7(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 NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 6 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 -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 rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.476-226C>T		intron_variant	Intron 6 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.476-226C>T		intron_variant	Intron 6 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.476-226C>T		intron_variant	Intron 6 of 27			ENSP00000513014.1

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

African (AFR) AF: 0.352 AC: 14582 AN: 41430

American (AMR) AF: 0.361 AC: 5512 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2052 AN: 3470

East Asian (EAS) AF: 0.395 AC: 2037 AN: 5154

South Asian (SAS) AF: 0.426 AC: 2050 AN: 4812

European-Finnish (FIN) AF: 0.592 AC: 6241 AN: 10548

Middle Eastern (MID) AF: 0.507 AC: 147 AN: 290

European-Non Finnish (NFE) AF: 0.501 AC: 34043 AN: 67934

Other (OTH) AF: 0.460 AC: 971 AN: 2112

Alfa AF: 0.425 Hom.: 4575

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
PhyloP100		-0.24
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: rs2424992; hg19: chr20-33012060;