3-100310515-T-AA

Variant names:

• chr3-100310515-T-AA
• rs1553730885
• NM_001199198.3:c.1526delTinsAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001199198.3(TBC1D23):​c.1526delTinsAA​(p.Ile509LysfsTer31) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBC1D23 NM_001199198.3 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

Genes affected

TBC1D23 (HGNC:25622): (TBC1 domain family member 23) Involved in brain development; retrograde transport, endosome to Golgi; and vesicle tethering to Golgi. Located in cytoplasmic vesicle and trans-Golgi network. Colocalizes with WASH complex. Implicated in pontocerebellar hypoplasia. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D23 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 11

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 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
• PP5: Variant 3-100310515-T-AA is Pathogenic according to our data. Variant chr3-100310515-T-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 397554.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D23	NM_001199198.3	c.1526delTinsAA	p.Ile509LysfsTer31	frameshift_variant, missense_variant	Exon 14 of 19	ENST00000394144.9	NP_001186127.1
TBC1D23	NM_018309.5	c.1526delTinsAA	p.Ile509LysfsTer16	frameshift_variant, missense_variant	Exon 14 of 18		NP_060779.2
TBC1D23	XM_047448562.1	c.962delTinsAA	p.Ile321LysfsTer31	frameshift_variant, missense_variant	Exon 11 of 16		XP_047304518.1
TBC1D23	XM_017006841.3	c.827delTinsAA	p.Ile276LysfsTer31	frameshift_variant, missense_variant	Exon 10 of 15		XP_016862330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D23	ENST00000394144.9	c.1526delTinsAA	p.Ile509LysfsTer31	frameshift_variant, missense_variant	Exon 14 of 19	1	NM_001199198.3	ENSP00000377700.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pontocerebellar hypoplasia, type 11 Pathogenic:1

Sep 29, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pontoneocerebellar hypoplasia Pathogenic:1

Jan 02, 2016

Chelly Lab, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg University - CNRS UMR 7104 - Inserm U 964

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553730885; hg19: chr3-100029359;