chrX-102749951-A-G

Variant names:

• chrX-102749951-A-G
• rs749186881
• NM_001142524.2:c.956A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142524.2(GPRASP3):​c.956A>G​(p.Tyr319Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,237 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y319S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPRASP3 NM_001142524.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

Genes affected

GPRASP3 (HGNC:29353): (G protein-coupled receptor associated sorting protein family member 3) This gene is a member of a gene family which encodes proteins with a basic helix-loop-helix domain. Other members of this gene family encode proteins which function as transcription factors, either enhancing or inhibiting transcription depending on the activity of other DNA binding proteins. The coding region of this gene is located entirely within the terminal exon. The encoded protein may be involved in the survival of neurons (PMID: 15034937). Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2011]

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]

LINC00630 (HGNC:44263): (long intergenic non-protein coding RNA 630)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102665484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142524.2. 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
	GPRASP3	NM_001142524.2	MANE Select	c.956A>G	p.Tyr319Cys	missense	Exon 4 of 4	NP_001135996.1	Q6PI77
	GPRASP3	NM_001142525.2		c.956A>G	p.Tyr319Cys	missense	Exon 4 of 4	NP_001135997.1	Q6PI77
	GPRASP3	NM_001142526.2		c.956A>G	p.Tyr319Cys	missense	Exon 4 of 4	NP_001135998.1	Q6PI77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPRASP3	ENST00000457056.6	TSL:4 MANE Select	c.956A>G	p.Tyr319Cys	missense	Exon 4 of 4	ENSP00000403226.1	Q6PI77
	GPRASP3	ENST00000361229.8	TSL:1	c.956A>G	p.Tyr319Cys	missense	Exon 3 of 3	ENSP00000354675.4	Q6PI77
	ARMCX5-GPRASP2	ENST00000652409.1		c.956A>G	p.Tyr319Cys	missense	Exon 8 of 8	ENSP00000498643.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112237 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000557 AC: 1 AN: 179404 AF XY: 0.0000156

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: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.13e-7 AC: 1 AN: 1095264 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 360882

African (AFR) AF: 0.00 AC: 0 AN: 26303

American (AMR) AF: 0.00 AC: 0 AN: 34608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19161

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53609

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840850

Other (OTH) AF: 0.00 AC: 0 AN: 45960

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112237 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34389

African (AFR) AF: 0.00 AC: 0 AN: 30844

American (AMR) AF: 0.00 AC: 0 AN: 10613

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2705

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53285

Other (OTH) AF: 0.00 AC: 0 AN: 1519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.025
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.34		Loss of phosphorylation at Y319 (P = 0.0506)
MVP		0.36
MPC		0.13
ClinPred		0.057	T
GERP RS		1.0
Varity_R		0.21
gMVP		0.13
Mutation Taster		=99/1	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: rs749186881; hg19: chrX-102004879;