21-33750259-G-T

Position:

• chr21-33750259-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003024.3(ITSN1):​c.463G>T​(p.Val155Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ITSN1 NM_003024.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14014336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITSN1	NM_003024.3	c.463G>T	p.Val155Leu	missense_variant	6/40	ENST00000381318.8	NP_003015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITSN1	ENST00000381318.8	c.463G>T	p.Val155Leu	missense_variant	6/40	1	NM_003024.3	ENSP00000370719.3
ENSG00000249209	ENST00000429238.2	c.441+157082C>A		intron_variant		5		ENSP00000394107.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome (MONDO#0005377), ITSN1-related and neurodevelopmental disorder (MONDO#0700092), ITSN1-related. (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants cause autosomal recessive nephrotic syndrome (MONDO#0005377), ITSN1-related, while monoallelic variants cause autosomal dominant neurodevelopmental disorder (MONDO#0700092), ITSN1-related (PMIDs: 29773874, 30721404, 34707297). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.70
DEOGEN2	Benign	0.065	.;T;.;T;.;.;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	.;N;N;.;N;N;.;N;N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.35	N;N;N;.;N;N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.64	T;T;T;.;T;T;T;T;T;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T
Polyphen		0.018, 0.030	.;B;.;.;.;.;B;B;.;.
Vest4		0.53
MutPred		0.14		.;Loss of catalytic residue at V155 (P = 0.0392);Loss of catalytic residue at V155 (P = 0.0392);.;Loss of catalytic residue at V155 (P = 0.0392);Loss of catalytic residue at V155 (P = 0.0392);Loss of catalytic residue at V155 (P = 0.0392);Loss of catalytic residue at V155 (P = 0.0392);Loss of catalytic residue at V155 (P = 0.0392);.;
MVP		0.60
MPC		0.35
ClinPred		0.57	D
GERP RS		5.2
Varity_R		0.15
gMVP		0.36

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.

Other links and lift over

hg19: chr21-35122564;