20-34480695-A-C

Variant names:

• chr20-34480695-A-C
• rs139633287
• NM_031483.7:c.1915A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031483.7(ITCH):​c.1915A>C​(p.Ile639Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I639V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITCH NM_031483.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47
• 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ENSG00000289720 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1915A>C	p.Ile639Leu	missense	Exon 19 of 25	NP_113671.3
	ITCH	NM_001257137.3		c.2038A>C	p.Ile680Leu	missense	Exon 20 of 26	NP_001244066.1	Q96J02-1
	ITCH	NM_001324197.2		c.2038A>C	p.Ile680Leu	missense	Exon 20 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.1915A>C	p.Ile639Leu	missense	Exon 19 of 25	ENSP00000363998.4	Q96J02-2
	ITCH	ENST00000262650.11	TSL:1	c.2038A>C	p.Ile680Leu	missense	Exon 20 of 26	ENSP00000262650.5	Q96J02-1
	ENSG00000289720	ENST00000696979.1		n.1915A>C		non_coding_transcript_exon	Exon 19 of 28	ENSP00000513014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PhyloP100		4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.049	D
Sift4G	Uncertain	0.013	D
Polyphen		0.0040	B
Vest4		0.41
MutPred		0.65		Loss of methylation at K675 (P = 0.0725)
MVP		0.77
MPC		1.0
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.60
Mutation Taster		=70/30	polymorphism

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: rs139633287; hg19: chr20-33068500;