21-33722604-CTT-CT
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5
The NM_003024.3(ITSN1):c.147delT(p.Gln50AsnfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000644 in 1,351,052 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
ITSN1
NM_003024.3 frameshift
NM_003024.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.16
Publications
1 publications found
Genes affected
ITSN1 (HGNC:6183): (intersectin 1) The protein encoded by this gene is a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery. In addition, the encoded protein may regulate the formation of clathrin-coated vesicles and could be involved in synaptic vesicle recycling. This protein has been shown to interact with dynamin, CDC42, SNAP23, SNAP25, SPIN90, EPS15, EPN1, EPN2, and STN2. Multiple transcript variants encoding different isoforms have been found for this gene, but the full-length nature of only two of them have been characterized so far. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 21-33722604-CT-C is Pathogenic according to our data. Variant chr21-33722604-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4056867.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_003024.3. 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 |
|---|---|---|---|---|---|---|---|---|---|
| ITSN1 | NM_003024.3 | MANE Select | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 40 | NP_003015.2 | ||
| ITSN1 | NM_001331010.2 | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 39 | NP_001317939.1 | Q15811-8 | ||
| ITSN1 | NM_001001132.2 | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 30 | NP_001001132.1 | Q15811-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ITSN1 | ENST00000381318.8 | TSL:1 MANE Select | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 40 | ENSP00000370719.3 | Q15811-1 | |
| ITSN1 | ENST00000399367.7 | TSL:1 | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 39 | ENSP00000382301.3 | Q15811-8 | |
| ITSN1 | ENST00000381291.8 | TSL:1 | c.147delT | p.Gln50AsnfsTer9 | frameshift | Exon 4 of 30 | ENSP00000370691.4 | Q15811-2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.000206 AC: 40AN: 194462 AF XY: 0.000122 show subpopulations
GnomAD2 exomes
AF:
AC:
40
AN:
194462
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000644 AC: 87AN: 1351052Hom.: 0 Cov.: 35 AF XY: 0.0000417 AC XY: 28AN XY: 670764 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
87
AN:
1351052
Hom.:
Cov.:
35
AF XY:
AC XY:
28
AN XY:
670764
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
2
AN:
28658
American (AMR)
AF:
AC:
24
AN:
32486
Ashkenazi Jewish (ASJ)
AF:
AC:
4
AN:
22126
East Asian (EAS)
AF:
AC:
0
AN:
33924
South Asian (SAS)
AF:
AC:
12
AN:
72934
European-Finnish (FIN)
AF:
AC:
3
AN:
46902
Middle Eastern (MID)
AF:
AC:
0
AN:
5194
European-Non Finnish (NFE)
AF:
AC:
38
AN:
1054926
Other (OTH)
AF:
AC:
4
AN:
53902
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.243
Heterozygous variant carriers
0
14
29
43
58
72
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
1
-
-
Inborn genetic diseases (1)
-
1
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.