X-102655460-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001184727.2(GPRASP1):c.1547C>G(p.Thr516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,209,152 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 180 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (0 hom. 173 hem.)
• Consequence: GPRASP1 NM_001184727.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.439

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02278784).
• BP6: Variant X-102655460-C-G is Benign according to our data. Variant chrX-102655460-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2372901.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRASP1	NM_001184727.2	c.1547C>G	p.Thr516Ser	missense_variant	6/6	ENST00000537097.2
ARMCX5-GPRASP2	NR_146584.3	n.649+49807C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRASP1	ENST00000537097.2	c.1547C>G	p.Thr516Ser	missense_variant	6/6	2	NM_001184727.2	P1
	ENST00000602441.1	n.57+4196G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000234 AC: 26 AN: 111170 Hom.: 0 Cov.: 23 AF XY: 0.000209 AC XY: 7 AN XY: 33418

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000415

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000234 AC: 43 AN: 183521 Hom.: 0 AF XY: 0.000221 AC XY: 15 AN XY: 67951

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000523 AC: 574 AN: 1097982 Hom.: 0 Cov.: 32 AF XY: 0.000476 AC XY: 173 AN XY: 363336

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000613

Gnomad4 OTH exome AF: 0.000933

GnomAD4 genome AF: 0.000234 AC: 26 AN: 111170 Hom.: 0 Cov.: 23 AF XY: 0.000209 AC XY: 7 AN XY: 33418

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000286

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000415

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000509 Hom.: 11

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.1547C>G (p.T516S) alteration is located in exon 6 (coding exon 1) of the GPRASP1 gene. This alteration results from a C to G substitution at nucleotide position 1547, causing the threonine (T) at amino acid position 516 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

GPRASP1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.93
Cadd	Benign	9.4
Dann	Benign	0.87
DEOGEN2	Benign	0.056	T;T;T;T
FATHMM_MKL	Benign	0.26	N
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.54	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.028	B;B;B;B
Vest4		0.094
MutPred		0.35		Gain of glycosylation at T516 (P = 0.0142);Gain of glycosylation at T516 (P = 0.0142);Gain of glycosylation at T516 (P = 0.0142);Gain of glycosylation at T516 (P = 0.0142);
MVP		0.33
MPC		0.12
ClinPred		0.011	T
GERP RS		2.8
Varity_R		0.094

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: rs202020063; hg19: chrX-101910388;