NM_003024.3:c.147dupT

Variant names:

• chr21-33722604-C-CT
• rs746959118
• NM_003024.3:c.147dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

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. 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 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ENSG00000249209 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.147dupT	p.Gln50SerfsTer17	frameshift	Exon 4 of 40	NP_003015.2
	ITSN1	NM_001331010.2		c.147dupT	p.Gln50SerfsTer17	frameshift	Exon 4 of 39	NP_001317939.1	Q15811-8
	ITSN1	NM_001001132.2		c.147dupT	p.Gln50SerfsTer17	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.147dupT	p.Gln50SerfsTer17	frameshift	Exon 4 of 40	ENSP00000370719.3	Q15811-1
	ITSN1	ENST00000399367.7	TSL:1	c.147dupT	p.Gln50SerfsTer17	frameshift	Exon 4 of 39	ENSP00000382301.3	Q15811-8
	ITSN1	ENST00000381291.8	TSL:1	c.147dupT	p.Gln50SerfsTer17	frameshift	Exon 4 of 30	ENSP00000370691.4	Q15811-2

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144242 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000375 AC: 73 AN: 194462 AF XY: 0.000328

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.000749

Gnomad ASJ exome AF: 0.000259

Gnomad EAS exome AF: 0.000682

Gnomad FIN exome AF: 0.0000500

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000189 AC: 255 AN: 1350280 Hom.: 0 Cov.: 35 AF XY: 0.000213 AC XY: 143 AN XY: 670366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000349 AC: 10 AN: 28632

American (AMR) AF: 0.000923 AC: 30 AN: 32490

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 6 AN: 22120

East Asian (EAS) AF: 0.000354 AC: 12 AN: 33896

South Asian (SAS) AF: 0.000673 AC: 49 AN: 72844

European-Finnish (FIN) AF: 0.000128 AC: 6 AN: 46870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.000124 AC: 131 AN: 1054390

Other (OTH) AF: 0.000204 AC: 11 AN: 53846

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000693 AC: 1 AN: 144242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 69932

African (AFR) AF: 0.0000256 AC: 1 AN: 39010

American (AMR) AF: 0.00 AC: 0 AN: 14328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4772

South Asian (SAS) AF: 0.00 AC: 0 AN: 4350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66288

Other (OTH) AF: 0.00 AC: 0 AN: 1998

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs746959118; hg19: chr21-35094909; COSMIC: COSV101180469; COSMIC: COSV101180469;