20-34456979-C-G

Variant names:

• chr20-34456979-C-G
• rs6059850
• NM_031483.7:c.1211-411C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_031483.7(ITCH):​c.1211-411C>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 150,960 control chromosomes in the GnomAD database, including 15,459 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 (15459 hom., cov: 30)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• 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.1211-411C>G		intron_variant	Intron 12 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.1211-411C>G		intron_variant	Intron 12 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.1211-411C>G		intron_variant	Intron 12 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67033 AN: 150886 Hom.: 15465 Cov.: 30

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.454

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

GnomAD4 genome AF: 0.444 AC: 67035 AN: 150960 Hom.: 15459 Cov.: 30 AF XY: 0.447 AC XY: 32954 AN XY: 73702

African (AFR) AF: 0.338 AC: 13922 AN: 41212

American (AMR) AF: 0.360 AC: 5447 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2051 AN: 3470

East Asian (EAS) AF: 0.396 AC: 2038 AN: 5150

South Asian (SAS) AF: 0.425 AC: 2044 AN: 4804

European-Finnish (FIN) AF: 0.599 AC: 6061 AN: 10120

Middle Eastern (MID) AF: 0.503 AC: 146 AN: 290

European-Non Finnish (NFE) AF: 0.501 AC: 33988 AN: 67792

Other (OTH) AF: 0.456 AC: 956 AN: 2096

Alfa AF: 0.480 Hom.: 2216

Bravo AF: 0.421

Asia WGS AF: 0.408 AC: 1418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		0.30
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: rs6059850; hg19: chr20-33044784;