X-102654729-G-T

Variant summary

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

The NM_001184727.2(GPRASP1):c.816G>T(p.Trp272Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,208,063 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 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 0.00054 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.000058 (0 hom. 16 hem.)
• Consequence: GPRASP1 NM_001184727.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.664

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=0.032738417).
• BS2: High Hemizygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP1	NM_001184727.2	c.816G>T	p.Trp272Cys	missense_variant	6/6	ENST00000537097.2
ARMCX5-GPRASP2	NR_146584.3	n.649+49076G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP1	ENST00000537097.2	c.816G>T	p.Trp272Cys	missense_variant	6/6	2	NM_001184727.2	P1
	ENST00000602441.1	n.57+4927C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000538 AC: 60 AN: 111508 Hom.: 0 Cov.: 23 AF XY: 0.000534 AC XY: 18 AN XY: 33734

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000158 AC: 29 AN: 183478 Hom.: 0 AF XY: 0.0000883 AC XY: 6 AN XY: 67924

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000584 AC: 64 AN: 1096555 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 16 AN XY: 361931

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.000538 AC: 60 AN: 111508 Hom.: 0 Cov.: 23 AF XY: 0.000534 AC XY: 18 AN XY: 33734

Gnomad4 AFR AF: 0.00186

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.0000977 Hom.: 3

Bravo AF: 0.000854

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

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 02, 2023

The c.816G>T (p.W272C) alteration is located in exon 6 (coding exon 1) of the GPRASP1 gene. This alteration results from a G to T substitution at nucleotide position 816, causing the tryptophan (W) at amino acid position 272 to be replaced by a cysteine (C). 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	0.29
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Uncertain	0.52	D;D;D;D
FATHMM_MKL	Benign	0.071	N
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.033	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Benign	0.055
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.29
MutPred		0.29		Loss of MoRF binding (P = 0.0115);Loss of MoRF binding (P = 0.0115);Loss of MoRF binding (P = 0.0115);Loss of MoRF binding (P = 0.0115);
MVP		0.082
MPC		0.59
ClinPred		0.13	T
GERP RS		1.9
Varity_R		0.20

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: rs141632272; hg19: chrX-101909657;