rs6058029

Variant names:

• chr20-34381837-T-C
• rs6058029
• NM_031483.7:c.-21-11954T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-34381837-T-C
• chr20-34381837-T-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.-21-11954T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 149,298 control chromosomes in the GnomAD database, including 23,862 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 0.56 (23862 hom., cov: 25)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.411
• Publications: 5 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.-21-11954T>C		intron_variant	Intron 2 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.-21-11954T>C		intron_variant	Intron 2 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.-21-11954T>C		intron_variant	Intron 2 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 83367 AN: 149198 Hom.: 23816 Cov.: 25

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.559 AC: 83475 AN: 149298 Hom.: 23862 Cov.: 25 AF XY: 0.557 AC XY: 40461 AN XY: 72642

African (AFR) AF: 0.666 AC: 27006 AN: 40552

American (AMR) AF: 0.644 AC: 9613 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1416 AN: 3454

East Asian (EAS) AF: 0.605 AC: 3055 AN: 5048

South Asian (SAS) AF: 0.575 AC: 2695 AN: 4690

European-Finnish (FIN) AF: 0.418 AC: 4158 AN: 9948

Middle Eastern (MID) AF: 0.503 AC: 145 AN: 288

European-Non Finnish (NFE) AF: 0.500 AC: 33729 AN: 67422

Other (OTH) AF: 0.549 AC: 1135 AN: 2066

Alfa AF: 0.383 Hom.: 1097

Bravo AF: 0.579

Asia WGS AF: 0.588 AC: 2045 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.32
PhyloP100		-0.41
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: rs6058029; hg19: chr20-32969643;