Genetic Variant NM_003024.3:c.53C>A (chr21-33721202-C-A) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

ITSN1 links:

ENSG00000249209 (HGNC:):

ENSG00000249209 links:

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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
ITSN1	NM_003024.3 link	c.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
ITSN1	ENST00000381318.8 link	c.53C>A	p.Thr18Asn	missense_variant	Exon 3 of 40	1	NM_003024.3	ENSP00000370719.3		Q15811-1
ENSG00000249209	ENST00000429238.2 link	c.442-135021G>T		intron_variant	Intron 6 of 7	5		ENSP00000394107.2		H7C0C1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460942

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

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

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

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

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.51

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.0

M;.;M;M;.;M;M;.;M;.;.;M

PrimateAI

Uncertain

0.77

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over