X-102654344-C-G

Variant names:

• chrX-102654344-C-G
• rs749573637
• NM_001184727.2:c.431C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001184727.2(GPRASP1):​c.431C>G​(p.Thr144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,097,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000020 (0 hom. 11 hem.)
• Consequence: GPRASP1 NM_001184727.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00900
• Publications: 0 publications found

Genes affected

GPRASP1 (HGNC:24834): (G protein-coupled receptor associated sorting protein 1) This gene encodes a member of the GPRASP (G protein-coupled receptor associated sorting protein) family. The protein may modulate lysosomal sorting and functional down-regulation of a variety of G-protein coupled receptors. It targets receptors for degradation in lysosomes. The receptors interacting with this sorting protein include D2 dopamine receptor (DRD2), delta opioid receptor (OPRD1), beta-2 adrenergic receptor (ADRB2), D4 dopamine receptor (DRD4) and cannabinoid 1 receptor (CB1R). Multiple alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, May 2010]

ARMCX5-GPRASP2 (HGNC:42000): (ARMCX5-GPRASP2 readthrough) This locus represents naturally occurring readthrough transcription among the adjacent armadillo repeat containing, X-linked 5 (ARMCX5), G protein-coupled receptor associated sorting proteins 1 and 2 (GPRASP1 and GPRASP2), basic helix-loop-helix family member b9 (BHLHB9), and long intergenic non-protein coding RNA 630 (LINC00630) genes on chromosome X. Transcripts may make use of multiple alternative promoters and polyadenylation signals in this region. Readthrough transcripts may produce proteins identical to the proteins encoded by GPRASP2 or BHLHB9. [provided by RefSeq, Apr 2017]

ENSG00000271147 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06427759).
• BS2: High Hemizygotes in GnomAdExome4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184727.2. 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
	GPRASP1	NM_001184727.2	MANE Select	c.431C>G	p.Thr144Arg	missense	Exon 6 of 6	NP_001171656.1	Q5JY77
	GPRASP1	NM_001099410.2		c.431C>G	p.Thr144Arg	missense	Exon 4 of 4	NP_001092880.1	Q5JY77
	GPRASP1	NM_001099411.2		c.431C>G	p.Thr144Arg	missense	Exon 3 of 3	NP_001092881.1	Q5JY77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPRASP1	ENST00000537097.2	TSL:2 MANE Select	c.431C>G	p.Thr144Arg	missense	Exon 6 of 6	ENSP00000445683.1	Q5JY77
	GPRASP1	ENST00000361600.9	TSL:2	c.431C>G	p.Thr144Arg	missense	Exon 5 of 5	ENSP00000355146.4	Q5JY77
	GPRASP1	ENST00000415986.5	TSL:4	c.431C>G	p.Thr144Arg	missense	Exon 4 of 4	ENSP00000393691.1	Q5JY77

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183478 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 22 AN: 1097196 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 11 AN XY: 362568

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.0000226 AC: 19 AN: 841168

Other (OTH) AF: 0.00 AC: 0 AN: 46061

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.4
DANN	Benign	0.87
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.0090
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.043
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.23	T
Polyphen		0.73	P
Vest4		0.15
MutPred		0.25		Loss of phosphorylation at T144 (P = 0.0554)
MVP		0.11
MPC		0.15
ClinPred		0.049	T
GERP RS		0.89
Varity_R		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs749573637; hg19: chrX-101909272;