11-18934381-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001393578.1(MRGPRX1):c.404C>T(p.Pro135Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MRGPRX1 NM_001393578.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRGPRX1	NM_001393578.1	c.404C>T	p.Pro135Leu	missense_variant	2/2	ENST00000526914.2
MRGPRX1	NM_147199.4	c.404C>T	p.Pro135Leu	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRGPRX1	ENST00000526914.2	c.404C>T	p.Pro135Leu	missense_variant	2/2	3	NM_001393578.1	P1
MRGPRX1	ENST00000302797.4	c.404C>T	p.Pro135Leu	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250708 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459356 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 726010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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

Aug 09, 2021

The c.404C>T (p.P135L) alteration is located in exon 1 (coding exon 1) of the MRGPRX1 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 to be replaced by a leucine (L). 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	Benign	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0062	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.19
Sift	Benign	0.049	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.78		Gain of catalytic residue at P135 (P = 0.0461);
MVP		0.54
MPC		0.25
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.46
gMVP		0.46

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: rs765623247; hg19: chr11-18955928;