rs6088512

Variant names:

• chr20-34508086-G-A
• rs6088512
• NM_031483.7:c.*292G>A

Variant summary

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

The NM_031483.7(ITCH):​c.*292G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 374,436 control chromosomes in the GnomAD database, including 45,949 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 0.48 (17901 hom., cov: 32)
  • Exomes 𝑓: 0.50 (28048 hom.)
• Consequence: ITCH NM_031483.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• Publications: 21 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000289720 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 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.*292G>A		3_prime_UTR	Exon 25 of 25	NP_113671.3
	ITCH	NM_001257137.3		c.*292G>A		3_prime_UTR	Exon 26 of 26	NP_001244066.1	Q96J02-1
	ITCH	NM_001324197.2		c.*292G>A		3_prime_UTR	Exon 26 of 26	NP_001311126.1	Q96J02-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITCH	ENST00000374864.10	TSL:1 MANE Select	c.*292G>A		3_prime_UTR	Exon 25 of 25	ENSP00000363998.4	Q96J02-2
	ITCH	ENST00000262650.11	TSL:1	c.*292G>A		3_prime_UTR	Exon 26 of 26	ENSP00000262650.5	Q96J02-1
	ENSG00000289720	ENST00000696979.1		n.*114+178G>A		intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73120 AN: 151978 Hom.: 17879 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.488

GnomAD4 exome AF: 0.498 AC: 110617 AN: 222340 Hom.: 28048 Cov.: 0 AF XY: 0.497 AC XY: 59855 AN XY: 120472

African (AFR) AF: 0.478 AC: 3082 AN: 6446

American (AMR) AF: 0.327 AC: 3436 AN: 10494

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 3547 AN: 5918

East Asian (EAS) AF: 0.383 AC: 4307 AN: 11232

South Asian (SAS) AF: 0.482 AC: 18452 AN: 38304

European-Finnish (FIN) AF: 0.582 AC: 6005 AN: 10318

Middle Eastern (MID) AF: 0.569 AC: 469 AN: 824

European-Non Finnish (NFE) AF: 0.514 AC: 65451 AN: 127252

Other (OTH) AF: 0.508 AC: 5868 AN: 11552

GnomAD4 genome AF: 0.481 AC: 73182 AN: 152096 Hom.: 17901 Cov.: 32 AF XY: 0.484 AC XY: 35994 AN XY: 74338

African (AFR) AF: 0.458 AC: 19017 AN: 41498

American (AMR) AF: 0.374 AC: 5710 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2043 AN: 5176

South Asian (SAS) AF: 0.458 AC: 2206 AN: 4818

European-Finnish (FIN) AF: 0.593 AC: 6263 AN: 10568

Middle Eastern (MID) AF: 0.517 AC: 151 AN: 292

European-Non Finnish (NFE) AF: 0.505 AC: 34309 AN: 67972

Other (OTH) AF: 0.490 AC: 1033 AN: 2110

Alfa AF: 0.494 Hom.: 23983

Bravo AF: 0.463

Asia WGS AF: 0.436 AC: 1517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.43
PhyloP100		-0.29
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: rs6088512; hg19: chr20-33095891;