11-18934406-G-A

Position:

• chr11-18934406-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.379C>T​(p.Pro127Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MRGPRX1 NM_001393578.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRGPRX1	NM_001393578.1	c.379C>T	p.Pro127Ser	missense_variant	2/2	ENST00000526914.2	NP_001380507.1
MRGPRX1	NM_147199.4	c.379C>T	p.Pro127Ser	missense_variant	1/1		NP_671732.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRGPRX1	ENST00000526914.2	c.379C>T	p.Pro127Ser	missense_variant	2/2	3	NM_001393578.1	ENSP00000499076.2
MRGPRX1	ENST00000302797.4	c.379C>T	p.Pro127Ser	missense_variant	1/1	6		ENSP00000305766.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

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

Mar 30, 2024

The c.379C>T (p.P127S) 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 379, causing the proline (P) at amino acid position 127 to be replaced by a serine (S). 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	0.60
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0058	T
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.29
Sift	Uncertain	0.029	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.88		Gain of MoRF binding (P = 0.0497);
MVP		0.83
MPC		0.26
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.48
gMVP		0.32

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: rs1848820378; hg19: chr11-18955953; COSMIC: COSV57108682; COSMIC: COSV57108682;