chr1-100539839-C-A

Variant names:

• chr1-100539839-C-A
• rs875989788
• NM_022049.3:c.873C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_022049.3(GPR88):​c.873C>A​(p.Cys291*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,405,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GPR88 NM_022049.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.890
• Publications: 3 publications found

Genes affected

GPR88 (HGNC:4539): (G protein-coupled receptor 88) The protein encoded by this gene is a G protein-coupled receptor found almost exclusively in the striatum, a brain structure that controls motor function and cognition. Defects in this gene have been associated with chorea, speech delay, and learning difficulties, as well as some neuropsychiatric disorders. [provided by RefSeq, Mar 2017]

GPR88 Gene-Disease associations (from GenCC):

• chorea, childhood-onset, with psychomotor retardation

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-100539839-C-A is Pathogenic according to our data. Variant chr1-100539839-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225846.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR88	NM_022049.3	c.873C>A	p.Cys291*	stop_gained	Exon 2 of 2	ENST00000315033.5	NP_071332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR88	ENST00000315033.5	c.873C>A	p.Cys291*	stop_gained	Exon 2 of 2	1	NM_022049.3	ENSP00000314223.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1405902 Hom.: 0 Cov.: 32 AF XY: 0.00000286 AC XY: 2 AN XY: 699390

African (AFR) AF: 0.00 AC: 0 AN: 29280

American (AMR) AF: 0.00 AC: 0 AN: 40056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24860

East Asian (EAS) AF: 0.00 AC: 0 AN: 34406

South Asian (SAS) AF: 0.00 AC: 0 AN: 81976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4852

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1095018

Other (OTH) AF: 0.00 AC: 0 AN: 58400

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chorea, childhood-onset, with psychomotor retardation Pathogenic:1

Jun 06, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	0.13
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.69	D
PhyloP100		-0.89
Vest4		0.65
GERP RS		2.0
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs875989788; hg19: chr1-101005395;