chrX-102750050-A-G

Variant names:

• chrX-102750050-A-G
• rs146078473
• NM_001142524.2:c.1055A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142524.2(GPRASP3):​c.1055A>G​(p.Asn352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,200,521 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N352K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 49 hem.)
• Consequence: GPRASP3 NM_001142524.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020377517).
• BS2: High Hemizygotes in GnomAdExome4 at 49 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.1055A>G	p.Asn352Ser	missense	Exon 4 of 4	NP_001135996.1	Q6PI77
	GPRASP3	NM_001142525.2		c.1055A>G	p.Asn352Ser	missense	Exon 4 of 4	NP_001135997.1	Q6PI77
	GPRASP3	NM_001142526.2		c.1055A>G	p.Asn352Ser	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.1055A>G	p.Asn352Ser	missense	Exon 4 of 4	ENSP00000403226.1	Q6PI77
	GPRASP3	ENST00000361229.8	TSL:1	c.1055A>G	p.Asn352Ser	missense	Exon 3 of 3	ENSP00000354675.4	Q6PI77
	ARMCX5-GPRASP2	ENST00000652409.1		c.1055A>G	p.Asn352Ser	missense	Exon 8 of 8	ENSP00000498643.1

Frequencies

GnomAD3 genomes AF: 0.0000714 AC: 8 AN: 112042 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000325

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: 0.000131

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000273 AC: 47 AN: 172335 AF XY: 0.000172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000980

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000148 AC: 161 AN: 1088479 Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 49 AN XY: 355449

African (AFR) AF: 0.0000384 AC: 1 AN: 26060

American (AMR) AF: 0.00103 AC: 35 AN: 33834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18763

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.00 AC: 0 AN: 52522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.000145 AC: 121 AN: 837215

Other (OTH) AF: 0.0000877 AC: 4 AN: 45607

GnomAD4 genome AF: 0.0000714 AC: 8 AN: 112042 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34204

African (AFR) AF: 0.0000325 AC: 1 AN: 30787

American (AMR) AF: 0.00 AC: 0 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53242

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

Alfa AF: 0.000157 Hom.: 2

Bravo AF: 0.000128

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000305 AC: 37

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.87
DANN	Benign	0.87
DEOGEN2	Benign	0.0040	T
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	0.11	T
Polyphen		0.39	B
Vest4		0.17
MVP		0.58
MPC		0.11
ClinPred		0.035	T
GERP RS		4.5
Varity_R		0.033
gMVP		0.25
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: rs146078473; hg19: chrX-102004978; COSMIC: COSV100771884; COSMIC: COSV100771884;