rs875989840

Variant names:

• chr6-165416280-A-G
• rs875989840
• NM_001385079.1:c.1798T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_001385079.1(PDE10A):​c.1798T>C​(p.Phe600Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F600C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE10A NM_001385079.1 missense, splice_region
• Scores: Splicing: ADA: 0.07795
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.99
• Publications: 8 publications found

Genes affected

PDE10A (HGNC:8772): (phosphodiesterase 10A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5' monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2011]

PDE10A Gene-Disease associations (from GenCC):

• striatal degeneration, autosomal dominant 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dyskinesia, limb and orofacial, infantile-onset

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• infantile-onset generalized dyskinesia with orofacial involvement

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood-onset benign chorea with striatal involvement

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-165416279-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 6-165416280-A-G is Pathogenic according to our data. Variant chr6-165416280-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385079.1. 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
	PDE10A	NM_001385079.1	MANE Select	c.1798T>C	p.Phe600Leu	missense splice_region	Exon 12 of 22	NP_001372008.1	Q9Y233-3
	PDE10A	NM_001130690.3		c.1000T>C	p.Phe334Leu	missense splice_region	Exon 12 of 22	NP_001124162.1	Q9Y233-2
	PDE10A	NM_006661.4		c.970T>C	p.Phe324Leu	missense splice_region	Exon 13 of 23	NP_006652.1	A0A1B1UZR0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE10A	ENST00000539869.4	TSL:1 MANE Select	c.1798T>C	p.Phe600Leu	missense splice_region	Exon 12 of 22	ENSP00000438284.3	Q9Y233-3
	PDE10A	ENST00000647768.3		c.1174T>C	p.Phe392Leu	missense splice_region	Exon 13 of 23	ENSP00000497930.3	A0A3B3ITT8
	PDE10A	ENST00000672902.1		c.1051T>C	p.Phe351Leu	missense splice_region	Exon 13 of 23	ENSP00000500351.1	A0A5F9ZHF9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Striatal degeneration, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.0
PrimateAI	Pathogenic	0.84	D
REVEL	Uncertain	0.52
Polyphen		0.59	P
MutPred		0.46		Loss of sheet (P = 0.0104)
MVP		0.64
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.078
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.0		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: rs875989840; hg19: chr6-165829768;