11-18934554-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001393578.1(MRGPRX1):c.231C>G(p.Ser77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MRGPRX1 NM_001393578.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682

Genes affected

MRGPRX1 (HGNC:17962): (MAS related GPR family member X1) Enables transmembrane signaling receptor activity. Involved in cell surface receptor signaling pathway and response to chloroquine. Predicted to be located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRGPRX1	NM_001393578.1	c.231C>G	p.Ser77Arg	missense_variant	2/2	ENST00000526914.2
MRGPRX1	NM_147199.4	c.231C>G	p.Ser77Arg	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRGPRX1	ENST00000526914.2	c.231C>G	p.Ser77Arg	missense_variant	2/2	3	NM_001393578.1	P1
MRGPRX1	ENST00000302797.4	c.231C>G	p.Ser77Arg	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458218 Hom.: 0 Cov.: 54 AF XY: 0.00000138 AC XY: 1 AN XY: 725392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000824 AC: 1

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

May 30, 2023

The c.231C>G (p.S77R) alteration is located in exon 1 (coding exon 1) of the MRGPRX1 gene. This alteration results from a C to G substitution at nucleotide position 231, causing the serine (S) at amino acid position 77 to be replaced by an arginine (R). 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0043	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.028	D
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.35
MutPred		0.75		Gain of methylation at S77 (P = 0.0076);
MVP		0.31
MPC		0.23
ClinPred		0.47	T
GERP RS		0.28
Varity_R		0.35
gMVP		0.27

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: rs776577056; hg19: chr11-18956101;