chr21-33721202-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003024.3(ITSN1):​c.53C>A​(p.Thr18Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ITSN1
NM_003024.3 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITSN1NM_003024.3 linkc.53C>A p.Thr18Asn missense_variant Exon 3 of 40 ENST00000381318.8 NP_003015.2 Q15811-1Q6PD56

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITSN1ENST00000381318.8 linkc.53C>A p.Thr18Asn missense_variant Exon 3 of 40 1 NM_003024.3 ENSP00000370719.3 Q15811-1
ENSG00000249209ENST00000429238.2 linkc.442-135021G>T intron_variant Intron 6 of 7 5 ENSP00000394107.2 H7C0C1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460942
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Oct 02, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.13
.;T;T;.;T;.;.;.;.;.;T;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.51
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.35
T
MutationAssessor
Pathogenic
3.0
M;.;M;M;.;M;M;.;M;.;.;M
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.0030
D;T;D;D;D;D;D;D;D;T;D;D
Sift4G
Uncertain
0.0090
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.48, 0.68
.;.;P;.;.;.;.;.;P;.;.;.
Vest4
0.70
MutPred
0.38
Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);Gain of catalytic residue at T18 (P = 0.051);
MVP
0.55
MPC
0.40
ClinPred
0.91
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.54
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-35093507; API