rs1553731605

Variant names:

• chr3-100316189-T-A
• rs1553731605
• NM_001199198.3:c.1687+2T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-100316189-T-A
• chr3-100316189-T-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_001199198.3(TBC1D23):​c.1687+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001430746: "In vitro functional studies provide some evidence that the c.1687+2T>A variant may slightly impact protein function." PMID:28823706".

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBC1D23 NM_001199198.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.13
• 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001430746: "In vitro functional studies provide some evidence that the c.1687+2T>A variant may slightly impact protein function." PMID:28823706
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-100316189-T-A is Pathogenic according to our data. Variant chr3-100316189-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 440763.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199198.3. 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
	TBC1D23	NM_001199198.3	MANE Select	c.1687+2T>A		splice_donor intron	N/A	NP_001186127.1	Q9NUY8-1
	TBC1D23	NM_018309.5		c.1642+2T>A		splice_donor intron	N/A	NP_060779.2	Q9NUY8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D23	ENST00000394144.9	TSL:1 MANE Select	c.1687+2T>A		splice_donor intron	N/A	ENSP00000377700.4	Q9NUY8-1
	TBC1D23	ENST00000344949.9	TSL:1	c.1642+2T>A		splice_donor intron	N/A	ENSP00000340693.5	Q9NUY8-2
	TBC1D23	ENST00000963832.1		c.1687+2T>A		splice_donor intron	N/A	ENSP00000633891.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Pontocerebellar hypoplasia, type 11 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.1
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -2

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

Other links and lift over

dbSNP: rs1553731605; hg19: chr3-100035033;