NM_031483.7:c.1210+51C>T

Variant names:

• chr20-34449531-C-T
• rs3736762
• NM_031483.7:c.1210+51C>T

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.1210+51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,193,640 control chromosomes in the GnomAD database, including 143,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15737 hom., cov: 31)
  • Exomes 𝑓: 0.49 (127295 hom.)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 16 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=-0.9).
• BP6: Variant 20-34449531-C-T is Benign according to our data. Variant chr20-34449531-C-T is described in ClinVar as Benign. ClinVar VariationId is 2628156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	NM_031483.7	MANE Select	c.1210+51C>T		intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.1333+51C>T		intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.1333+51C>T		intron	N/A	NP_001311126.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.1210+51C>T		intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.1333+51C>T		intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.1210+51C>T		intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67888 AN: 151720 Hom.: 15730 Cov.: 31

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.458 AC: 109681 AN: 239352 AF XY: 0.468

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.488 AC: 507880 AN: 1041802 Hom.: 127295 Cov.: 14 AF XY: 0.489 AC XY: 261955 AN XY: 535980

African (AFR) AF: 0.357 AC: 9042 AN: 25352

American (AMR) AF: 0.263 AC: 11446 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 14138 AN: 23432

East Asian (EAS) AF: 0.363 AC: 13682 AN: 37690

South Asian (SAS) AF: 0.447 AC: 34307 AN: 76820

European-Finnish (FIN) AF: 0.584 AC: 30568 AN: 52312

Middle Eastern (MID) AF: 0.542 AC: 2640 AN: 4870

European-Non Finnish (NFE) AF: 0.505 AC: 369317 AN: 731396

Other (OTH) AF: 0.490 AC: 22740 AN: 46436

GnomAD4 genome AF: 0.447 AC: 67928 AN: 151838 Hom.: 15737 Cov.: 31 AF XY: 0.450 AC XY: 33408 AN XY: 74186

African (AFR) AF: 0.352 AC: 14563 AN: 41400

American (AMR) AF: 0.361 AC: 5507 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2050 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2037 AN: 5170

South Asian (SAS) AF: 0.427 AC: 2052 AN: 4810

European-Finnish (FIN) AF: 0.591 AC: 6210 AN: 10500

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34012 AN: 67928

Other (OTH) AF: 0.460 AC: 968 AN: 2106

Alfa AF: 0.469 Hom.: 7499

Bravo AF: 0.426

Asia WGS AF: 0.414 AC: 1440 AN: 3476

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	-0.90
CADD	Benign	0.81
DANN	Benign	0.49
PhyloP100		-1.0
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: rs3736762; hg19: chr20-33037336; COSMIC: COSV52932237; COSMIC: COSV52932237;