Variant 21-33750262-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003024.3(ITSN1):c.466C>T(p.Pro156Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ITSN1
NM_003024.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

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]

ITSN1 links:

ENSG00000249209 (HGNC:):

ENSG00000249209 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20875823).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITSN1	NM_003024.3 linkuse as main transcript	c.466C>T	p.Pro156Ser	missense_variant	6/40	ENST00000381318.8	NP_003015.2	Q15811-1Q6PD56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITSN1	ENST00000381318.8 linkuse as main transcript	c.466C>T	p.Pro156Ser	missense_variant	6/40	1	NM_003024.3	ENSP00000370719.3		Q15811-1
ENSG00000249209	ENST00000429238.2 linkuse as main transcript	c.441+157079G>A		intron_variant		5		ENSP00000394107.2		H7C0C1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726982

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:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.466C>T (p.P156S) alteration is located in exon 6 (coding exon 5) of the ITSN1 gene. This alteration results from a C to T substitution at nucleotide position 466, causing the proline (P) at amino acid position 156 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.22

.;T;.;T;.;.;.;.;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

T;D;D;T;D;D;D;D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.9

.;L;L;.;L;L;.;L;L;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.4

D;N;N;.;N;N;N;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.068

T;D;D;.;D;D;D;D;D;.

Sift4G

Uncertain

0.025

D;T;T;D;T;T;T;T;T;T

Polyphen

0.16, 0.39

.;B;.;.;.;.;B;B;.;.

Vest4

0.68

MutPred

0.25

.;Loss of catalytic residue at P156 (P = 0.0018);Loss of catalytic residue at P156 (P = 0.0018);.;Loss of catalytic residue at P156 (P = 0.0018);Loss of catalytic residue at P156 (P = 0.0018);Loss of catalytic residue at P156 (P = 0.0018);Loss of catalytic residue at P156 (P = 0.0018);Loss of catalytic residue at P156 (P = 0.0018);.;

MVP

0.58

MPC

0.36

ClinPred

0.75

GERP RS

3.3

Varity_R

0.18

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over