Genetic Variant NM_031483.7:c.71-1742A>G (chr20-34406909-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031483.7(ITCH):c.71-1742A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 151,932 control chromosomes in the GnomAD database, including 23,781 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 ( 23781 hom., cov: 31)

Consequence

ITCH
NM_031483.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.504

Publications

9 publications found

Variant links:

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

ITCH links:

ENSG00000289720 (HGNC:):

ENSG00000289720 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITCH	NM_031483.7 link	c.71-1742A>G		intron_variant	Intron 3 of 24	ENST00000374864.10	NP_113671.3	Q96J02-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITCH	ENST00000374864.10 link	c.71-1742A>G		intron_variant	Intron 3 of 24	1	NM_031483.7	ENSP00000363998.4		Q96J02-2
ENSG00000289720	ENST00000696979.1 link	n.71-1742A>G		intron_variant	Intron 3 of 27			ENSP00000513014.1

Frequencies

GnomAD3 genomes

AF:

0.553

AC:

83908

AN:

151814

Hom.:

23751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.649

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.638

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.604

Gnomad SAS

AF:

0.575

Gnomad FIN

AF:

0.408

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.499

Gnomad OTH

AF:

0.545

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

GnomAD4 genome

AF:

0.553

AC:

83993

AN:

151932

Hom.:

23781

Cov.:

AF XY:

0.550

AC XY:

40815

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.649

AC:

26874

AN:

41420

American (AMR)

AF:

0.639

AC:

9759

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

1419

AN:

3470

East Asian (EAS)

AF:

0.605

AC:

3124

AN:

5160

South Asian (SAS)

AF:

0.575

AC:

2768

AN:

4816

European-Finnish (FIN)

AF:

0.408

AC:

4302

AN:

10534

Middle Eastern (MID)

AF:

0.503

AC:

148

AN:

294

European-Non Finnish (NFE)

AF:

0.499

AC:

33928

AN:

67950

Other (OTH)

AF:

0.542

AC:

1142

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1895

3790

5684

7579

9474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.505

Hom.:

4686

Bravo

AF:

0.574

Asia WGS

AF:

0.589

AC:

2048

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

7.0

(source)

DANN

Benign

0.75

PhyloP100

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over