rs6087579

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	NM_031483.7	MANE Select	c.70+3468A>G		intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.70+3468A>G		intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.70+3468A>G		intron	N/A	NP_001311126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.70+3468A>G		intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.70+3468A>G		intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.70+3468A>G		intron	N/A	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

African (AFR) AF: 0.612 AC: 25354 AN: 41454

American (AMR) AF: 0.634 AC: 9685 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3134 AN: 5164

South Asian (SAS) AF: 0.571 AC: 2751 AN: 4818

European-Finnish (FIN) AF: 0.409 AC: 4309 AN: 10536

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.499 AC: 33901 AN: 67972

Other (OTH) AF: 0.529 AC: 1117 AN: 2110

Alfa AF: 0.509 Hom.: 3299

Bravo AF: 0.561

Asia WGS AF: 0.577 AC: 2005 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.39
PhyloP100		0.49
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: rs6087579; hg19: chr20-32985155;