rs746959118

Variant names:

• chr21-33722604-CTT-C
• rs746959118
• NM_003024.3:c.146_147delTT

Your query was ambiguous. Multiple possible variants found:

• chr21-33722604-CTT-C
• chr21-33722604-CTT-CT
• chr21-33722604-CTT-CTTT
• chr21-33722604-CTT-CTTTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003024.3(ITSN1):​c.146_147delTT​(p.Phe49SerfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000074 in 1,351,630 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ITSN1 NM_003024.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.146_147delTT	p.Phe49SerfsTer17	frameshift	Exon 4 of 40	NP_003015.2
	ITSN1	NM_001331010.2		c.146_147delTT	p.Phe49SerfsTer17	frameshift	Exon 4 of 39	NP_001317939.1	Q15811-8
	ITSN1	NM_001001132.2		c.146_147delTT	p.Phe49SerfsTer17	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.146_147delTT	p.Phe49SerfsTer17	frameshift	Exon 4 of 40	ENSP00000370719.3	Q15811-1
	ITSN1	ENST00000399367.7	TSL:1	c.146_147delTT	p.Phe49SerfsTer17	frameshift	Exon 4 of 39	ENSP00000382301.3	Q15811-8
	ITSN1	ENST00000381291.8	TSL:1	c.146_147delTT	p.Phe49SerfsTer17	frameshift	Exon 4 of 30	ENSP00000370691.4	Q15811-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1351630 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 671088

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

African (AFR) AF: 0.00 AC: 0 AN: 28670

American (AMR) AF: 0.00 AC: 0 AN: 32552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22148

East Asian (EAS) AF: 0.00 AC: 0 AN: 33942

South Asian (SAS) AF: 0.00 AC: 0 AN: 73014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5196

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1055246

Other (OTH) AF: 0.00 AC: 0 AN: 53932

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

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;