chr21-33722597-C-G

Position:

• chr21-33722597-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003024.3(ITSN1):​c.131C>G​(p.Ala44Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000427 in 1,405,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ITSN1 NM_003024.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITSN1	NM_003024.3	c.131C>G	p.Ala44Gly	missense_variant	4/40	ENST00000381318.8	NP_003015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITSN1	ENST00000381318.8	c.131C>G	p.Ala44Gly	missense_variant	4/40	1	NM_003024.3	ENSP00000370719.3
ENSG00000249209	ENST00000429238.2	c.442-136416G>C		intron_variant		5		ENSP00000394107.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1405956 Hom.: 0 Cov.: 35 AF XY: 0.00000286 AC XY: 2 AN XY: 698494

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: 0.00000551

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2024

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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;T;.;T;.;.;.;.;.;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.040	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;.;H;H;.;H;.;.;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96, 0.98	.;.;D;.;.;.;.;.;D;.;.;.
Vest4		0.88
MutPred		0.53		Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);Loss of catalytic residue at A44 (P = 0.0215);
MVP		0.84
MPC		0.35
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.87

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: chr21-35094902;