rs4911154

Variant names:

• chr20-34408295-G-A
• rs4911154
• NM_031483.7:c.71-356G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-34408295-G-A
• chr20-34408295-G-T

Variant summary

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

The NM_031483.7(ITCH):​c.71-356G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,016 control chromosomes in the GnomAD database, including 2,145 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 0.16 (2145 hom., cov: 32)
• Consequence: ITCH NM_031483.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.318 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.71-356G>A		intron	N/A	NP_113671.3
	ITCH	NM_001257137.3		c.71-356G>A		intron	N/A	NP_001244066.1
	ITCH	NM_001324197.2		c.71-356G>A		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.71-356G>A		intron	N/A	ENSP00000363998.4
	ITCH	ENST00000262650.11	TSL:1	c.71-356G>A		intron	N/A	ENSP00000262650.5
	ENSG00000289720	ENST00000696979.1		n.71-356G>A		intron	N/A	ENSP00000513014.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24101 AN: 151898 Hom.: 2146 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.159 AC: 24098 AN: 152016 Hom.: 2145 Cov.: 32 AF XY: 0.157 AC XY: 11670 AN XY: 74326

African (AFR) AF: 0.134 AC: 5570 AN: 41426

American (AMR) AF: 0.106 AC: 1616 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0885 AC: 307 AN: 3468

East Asian (EAS) AF: 0.178 AC: 919 AN: 5160

South Asian (SAS) AF: 0.332 AC: 1600 AN: 4826

European-Finnish (FIN) AF: 0.126 AC: 1328 AN: 10578

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.182 AC: 12381 AN: 67962

Other (OTH) AF: 0.136 AC: 286 AN: 2108

Alfa AF: 0.147 Hom.: 319

Bravo AF: 0.150

Asia WGS AF: 0.236 AC: 822 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.71
PhyloP100		0.087
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: rs4911154; hg19: chr20-32996101;