Genetic Variant NM_003024.3:c.147dupT (chr21-33722604-C-CT) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The NM_003024.3(ITSN1):c.147dupT(p.Gln50SerfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.000189 in 1,350,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITSN1
NM_003024.3 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000189 (255/1350280) while in subpopulation AMR AF= 0.000923 (30/32490). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4_exome. There are 143 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITSN1	NM_003024.3 link	c.147dupT	p.Gln50SerfsTer17	frameshift_variant	Exon 4 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.147dupT	p.Gln50SerfsTer17	frameshift_variant	Exon 4 of 40	1	NM_003024.3	ENSP00000370719.3		Q15811-1
ENSG00000249209	ENST00000429238.2 link	c.442-136424dupA		intron_variant	Intron 6 of 7	5		ENSP00000394107.2		H7C0C1

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000256

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000189

AC:

255

AN:

1350280

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

143

AN XY:

670366

show subpopulations

Gnomad4 AFR exome

AF:

0.000349

Gnomad4 AMR exome

AF:

0.000923

Gnomad4 ASJ exome

AF:

0.000271

Gnomad4 EAS exome

AF:

0.000354

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.000128

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.000204

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000693

AC:

AN:

144242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69932

show subpopulations

Gnomad4 AFR

AF:

0.0000256

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 06, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a study evaluating associations between loss-of-function variants in the ITSN1 gene and Parkinson's disease; however, specific clinical information was not provided (PMID: 39147844); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 39147844) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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