rs368463899

Variant names:

• chrX-102749560-A-C
• rs368463899
• NM_001142524.2:c.565A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-102749560-A-C
• chrX-102749560-A-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001142524.2(GPRASP3):​c.565A>C​(p.Asn189His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,209,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N189K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (0 hom. 58 hem.)
• Consequence: GPRASP3 NM_001142524.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.386
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18488505).
• BP6: Variant X-102749560-A-C is Benign according to our data. Variant chrX-102749560-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2661087.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

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.565A>C	p.Asn189His	missense	Exon 4 of 4	NP_001135996.1	Q6PI77
	GPRASP3	NM_001142525.2		c.565A>C	p.Asn189His	missense	Exon 4 of 4	NP_001135997.1	Q6PI77
	GPRASP3	NM_001142526.2		c.565A>C	p.Asn189His	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.565A>C	p.Asn189His	missense	Exon 4 of 4	ENSP00000403226.1	Q6PI77
	GPRASP3	ENST00000361229.8	TSL:1	c.565A>C	p.Asn189His	missense	Exon 3 of 3	ENSP00000354675.4	Q6PI77
	ARMCX5-GPRASP2	ENST00000652409.1		c.565A>C	p.Asn189His	missense	Exon 8 of 8	ENSP00000498643.1

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 12 AN: 111496 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 24 AN: 183496 AF XY: 0.0000736

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 198 AN: 1098226 Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 58 AN XY: 363582

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000221 AC: 186 AN: 842112

Other (OTH) AF: 0.000195 AC: 9 AN: 46098

GnomAD4 genome AF: 0.000108 AC: 12 AN: 111496 Hom.: 0 Cov.: 23 AF XY: 0.0000594 AC XY: 2 AN XY: 33684

African (AFR) AF: 0.0000654 AC: 2 AN: 30603

American (AMR) AF: 0.00 AC: 0 AN: 10538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6008

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

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53110

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.000218 Hom.: 1

Bravo AF: 0.000181

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.39
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.092
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.92	P
Vest4		0.16
MVP		0.61
MPC		0.37
ClinPred		0.14	T
GERP RS		-1.8
Varity_R		0.20
gMVP		0.22
Mutation Taster		=100/0	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: rs368463899; hg19: chrX-102004488;