rs6059866

Variant names:

• chr20-34488005-T-G
• rs6059866
• NM_031483.7:c.2094-1261T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031483.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	NM_031483.7	MANE Select	c.2094-1261T>G		intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.2217-1261T>G		intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.2217-1261T>G		intron	N/A	NP_001311126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.2094-1261T>G		intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.2217-1261T>G		intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.2094-1261T>G		intron	N/A	ENSP00000513014.1

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

African (AFR) AF: 0.337 AC: 13977 AN: 41488

American (AMR) AF: 0.360 AC: 5491 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2056 AN: 3468

East Asian (EAS) AF: 0.395 AC: 2046 AN: 5174

South Asian (SAS) AF: 0.426 AC: 2052 AN: 4812

European-Finnish (FIN) AF: 0.591 AC: 6223 AN: 10534

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34083 AN: 67948

Other (OTH) AF: 0.456 AC: 959 AN: 2104

Alfa AF: 0.441 Hom.: 3963

Bravo AF: 0.422

Asia WGS AF: 0.408 AC: 1421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.27
PhyloP100		0.27
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: rs6059866; hg19: chr20-33075810;