20-34410848-T-C

Variant names:

• chr20-34410848-T-C
• rs4911420
• NM_031483.7:c.213-1667T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001257137.3(ITCH):​c.213-1667T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 152,052 control chromosomes in the GnomAD database, including 23,354 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 0.55 (23354 hom., cov: 32)
• Consequence: ITCH NM_001257137.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.823
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257137.3. 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.213-1667T>C		intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.213-1667T>C		intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.213-1667T>C		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.213-1667T>C		intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.213-1667T>C		intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.213-1667T>C		intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83280 AN: 151934 Hom.: 23333 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.548 AC: 83346 AN: 152052 Hom.: 23354 Cov.: 32 AF XY: 0.545 AC XY: 40510 AN XY: 74320

African (AFR) AF: 0.634 AC: 26292 AN: 41488

American (AMR) AF: 0.637 AC: 9727 AN: 15270

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

East Asian (EAS) AF: 0.606 AC: 3131 AN: 5164

South Asian (SAS) AF: 0.571 AC: 2754 AN: 4820

European-Finnish (FIN) AF: 0.408 AC: 4313 AN: 10560

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

European-Non Finnish (NFE) AF: 0.499 AC: 33910 AN: 67964

Other (OTH) AF: 0.534 AC: 1128 AN: 2112

Alfa AF: 0.541 Hom.: 8588

Bravo AF: 0.569

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.9
DANN	Benign	0.90
PhyloP100		-0.82
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: rs4911420; hg19: chr20-32998654;