X-102654568-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001184727.2(GPRASP1):c.655G>A(p.Val219Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,209,132 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000042 (0 hom. 21 hem.)
• Consequence: GPRASP1 NM_001184727.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.231

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017871112).
• BS2: High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP1	NM_001184727.2	c.655G>A	p.Val219Ile	missense_variant	6/6	ENST00000537097.2
ARMCX5-GPRASP2	NR_146584.3	n.649+48915G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP1	ENST00000537097.2	c.655G>A	p.Val219Ile	missense_variant	6/6	2	NM_001184727.2	P1
	ENST00000602441.1	n.58-4854C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111708 Hom.: 0 Cov.: 23 AF XY: 0.0000591 AC XY: 2 AN XY: 33866

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000945

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000981 AC: 18 AN: 183396 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000419 AC: 46 AN: 1097368 Hom.: 0 Cov.: 30 AF XY: 0.0000579 AC XY: 21 AN XY: 362730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111764 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33932

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000944

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000212 Hom.: 1

Bravo AF: 0.0000604

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.655G>A (p.V219I) alteration is located in exon 6 (coding exon 1) of the GPRASP1 gene. This alteration results from a G to A substitution at nucleotide position 655, causing the valine (V) at amino acid position 219 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.16
Dann	Benign	0.61
DEOGEN2	Benign	0.042	T;T;T;T
FATHMM_MKL	Benign	0.0056	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.0040	B;B;B;B
Vest4		0.041
MutPred		0.18		Loss of methylation at K220 (P = 0.0652);Loss of methylation at K220 (P = 0.0652);Loss of methylation at K220 (P = 0.0652);Loss of methylation at K220 (P = 0.0652);
MVP		0.11
MPC		0.11
ClinPred		0.0069	T
GERP RS		-2.6
Varity_R		0.029

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

Publications

LitVar

Other links and lift over

dbSNP: rs747569317; hg19: chrX-101909496;