NM_003024.3:c.4341+48C>G

Variant names:

• chr21-33875569-C-G
• rs933130
• NM_003024.3:c.4341+48C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003024.3(ITSN1):​c.4341+48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 1,570,624 control chromosomes in the GnomAD database, including 225,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25788 hom., cov: 32)
  • Exomes 𝑓: 0.53 (199259 hom.)
• Consequence: ITSN1 NM_003024.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.894
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-33875569-C-G is Benign according to our data. Variant chr21-33875569-C-G is described in ClinVar as Benign. ClinVar VariationId is 1277247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITSN1	NM_003024.3	c.4341+48C>G		intron_variant	Intron 34 of 39	ENST00000381318.8	NP_003015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITSN1	ENST00000381318.8	c.4341+48C>G		intron_variant	Intron 34 of 39	1	NM_003024.3	ENSP00000370719.3
ENSG00000249209	ENST00000429238.2	c.441+31772G>C		intron_variant	Intron 6 of 7	5		ENSP00000394107.2

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87276 AN: 151918 Hom.: 25775 Cov.: 32

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.546

GnomAD2 exomes AF: 0.537 AC: 120593 AN: 224762 AF XY: 0.535

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.571

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.531

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.528 AC: 749552 AN: 1418588 Hom.: 199259 Cov.: 26 AF XY: 0.528 AC XY: 371436 AN XY: 703476

African (AFR) AF: 0.726 AC: 23460 AN: 32314

American (AMR) AF: 0.420 AC: 17102 AN: 40724

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 11526 AN: 24076

East Asian (EAS) AF: 0.570 AC: 22375 AN: 39270

South Asian (SAS) AF: 0.501 AC: 41085 AN: 81940

European-Finnish (FIN) AF: 0.605 AC: 31457 AN: 51986

Middle Eastern (MID) AF: 0.503 AC: 2738 AN: 5446

European-Non Finnish (NFE) AF: 0.525 AC: 568739 AN: 1084318

Other (OTH) AF: 0.531 AC: 31070 AN: 58514

GnomAD4 genome AF: 0.574 AC: 87333 AN: 152036 Hom.: 25788 Cov.: 32 AF XY: 0.574 AC XY: 42616 AN XY: 74308

African (AFR) AF: 0.718 AC: 29793 AN: 41468

American (AMR) AF: 0.454 AC: 6942 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3470

East Asian (EAS) AF: 0.567 AC: 2926 AN: 5160

South Asian (SAS) AF: 0.503 AC: 2420 AN: 4814

European-Finnish (FIN) AF: 0.614 AC: 6502 AN: 10584

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35292 AN: 67944

Other (OTH) AF: 0.545 AC: 1149 AN: 2110

Alfa AF: 0.452 Hom.: 2205

Bravo AF: 0.569

Asia WGS AF: 0.520 AC: 1811 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.29
PhyloP100		0.89
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs933130; hg19: chr21-35247873; COSMIC: COSV67157129;