20-34412546-CGT-AGA

Variant names:

• chr20-34412546-CGT-AGA
• NM_031483.7:c.244_246delCGTinsAGA
• ITCH p.83

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_031483.7(ITCH):​c.244_246delCGTinsAGA​(p.83) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R82R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITCH NM_031483.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.78
• Publications: 0 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000289720 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	NM_031483.7	MANE Select	c.244_246delCGTinsAGA	p.83	synonymous	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.244_246delCGTinsAGA	p.83	synonymous	N/A	NP_001244066.1	Q96J02-1
	ITCH	NM_001324197.2		c.244_246delCGTinsAGA	p.83	synonymous	N/A	NP_001311126.1	Q96J02-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.244_246delCGTinsAGA	p.83	synonymous	N/A	ENSP00000363998.4	Q96J02-2
	ITCH	ENST00000262650.11	TSL:1	c.244_246delCGTinsAGA	p.83	synonymous	N/A	ENSP00000262650.5	Q96J02-1
	ENSG00000289720	ENST00000696979.1		n.244_246delCGTinsAGA		non_coding_transcript_exon	Exon 5 of 28	ENSP00000513014.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-33000352;