X-102654535-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001184727.2(GPRASP1):c.622G>A(p.Glu208Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,208,952 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.00012 (0 hom. 44 hem.)
• Consequence: GPRASP1 NM_001184727.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14856723).
• BS2: High Hemizygotes in GnomAdExome at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP1	NM_001184727.2	c.622G>A	p.Glu208Lys	missense_variant	6/6	ENST00000537097.2
ARMCX5-GPRASP2	NR_146584.3	n.649+48882G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP1	ENST00000537097.2	c.622G>A	p.Glu208Lys	missense_variant	6/6	2	NM_001184727.2	P1
	ENST00000602441.1	n.58-4821C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 111827 Hom.: 0 Cov.: 24 AF XY: 0.0000294 AC XY: 1 AN XY: 33979

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 23 AN: 183382 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000118 AC: 129 AN: 1097125 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 44 AN XY: 362495

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.000206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000107 AC: 12 AN: 111827 Hom.: 0 Cov.: 24 AF XY: 0.0000294 AC XY: 1 AN XY: 33979

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000255 Hom.: 12

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000273

EpiControl AF: 0.000711

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

Feb 27, 2023

The c.622G>A (p.E208K) 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 622, causing the glutamic acid (E) at amino acid position 208 to be replaced by a lysine (K). 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	0.094
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.34
MVP		0.39
MPC		0.62
ClinPred		0.23	T
GERP RS		2.2
Varity_R		0.18

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: rs200333794; hg19: chrX-101909463;