NM_031483.7:c.70+3468A>G

Variant names:

• chr20-34397349-A-G
• rs6087579
• NM_031483.7:c.70+3468A>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]

ENSG00000289720 (HGNC:):

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 rank	MANE	Protein	UniProt
ITCH	NM_031483.7	c.70+3468A>G		intron_variant	Intron 3 of 24	ENST00000374864.10	NP_113671.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10	c.70+3468A>G		intron_variant	Intron 3 of 24	1	NM_031483.7	ENSP00000363998.4
ENSG00000289720	ENST00000696979.1	n.70+3468A>G		intron_variant	Intron 3 of 27			ENSP00000513014.1

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

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;