rs6087579

Positions:

• chr20-34397349-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031483.7(ITCH):​c.70+3468A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 152,002 control chromosomes in the GnomAD database, including 22,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (22729 hom., cov: 32)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.486

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-34397349-A-G is Benign according to our data. Variant chr20-34397349-A-G is described in ClinVar as [Benign]. Clinvar id is 2688542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITCH	NM_031483.7	c.70+3468A>G		intron_variant		ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.70+3468A>G		intron_variant		1	NM_031483.7	ENSP00000363998	P1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82282 AN: 151884 Hom.: 22710 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.532

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

GnomAD4 genome AF: 0.542 AC: 82343 AN: 152002 Hom.: 22729 Cov.: 32 AF XY: 0.539 AC XY: 40085 AN XY: 74318

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.571

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.529

Alfa AF: 0.507 Hom.: 3164

Bravo AF: 0.561

Asia WGS AF: 0.577 AC: 2005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 84% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
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: rs6087579; hg19: chr20-32985155;