rs6120644

Positions:

• chr20-34436005-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031483.7(ITCH):​c.522-2469G>A 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 151,896 control chromosomes in the GnomAD database, including 15,766 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 (15766 hom., cov: 31)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• 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/exons	MANE	UniProt
ITCH	NM_031483.7	c.522-2469G>A		intron_variant		ENST00000374864.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITCH	ENST00000374864.10	c.522-2469G>A		intron_variant		1	NM_031483.7	P1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67953 AN: 151778 Hom.: 15759 Cov.: 31

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.456

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

GnomAD4 genome AF: 0.448 AC: 67991 AN: 151896 Hom.: 15766 Cov.: 31 AF XY: 0.451 AC XY: 33444 AN XY: 74206

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.393

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.459

Alfa AF: 0.460 Hom.: 4865

Bravo AF: 0.427

Asia WGS AF: 0.412 AC: 1433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs6120644; hg19: chr20-33023810;