11-18137236-C-G

Variant names:

• chr11-18137236-C-G
• rs1438441396
• NM_001370464.1:c.34C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370464.1(MRGPRX3):​c.34C>G​(p.Leu12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,188 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRGPRX3 NM_001370464.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.88

Genes affected

MRGPRX3 (HGNC:17980): (MAS related GPR family member X3) This gene encodes a member of the mas-related/sensory neuron specific subfamily of G protein coupled receptors. The encoded protein may be involved in sensory neuron regulation and in the modulation of pain. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047446966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRGPRX3	NM_001370464.1	c.34C>G	p.Leu12Val	missense_variant	Exon 2 of 2	ENST00000621697.2	NP_001357393.1
MRGPRX3	NM_054031.4	c.34C>G	p.Leu12Val	missense_variant	Exon 3 of 3		NP_473372.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRGPRX3	ENST00000621697.2	c.34C>G	p.Leu12Val	missense_variant	Exon 2 of 2	2	NM_001370464.1	ENSP00000481943.1
MRGPRX3	ENST00000396275.2	c.34C>G	p.Leu12Val	missense_variant	Exon 3 of 3	1		ENSP00000379571.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459188 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725712

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>G (p.L12V) alteration is located in exon 3 (coding exon 1) of the MRGPRX3 gene. This alteration results from a C to G substitution at nucleotide position 34, causing the leucine (L) at amino acid position 12 to be replaced by a valine (V). 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	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.11
DANN	Benign	0.44
DEOGEN2	Benign	0.0043	T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.095	.;T;T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.40	N;N;.
REVEL	Benign	0.013
Sift	Benign	0.53	T;T;.
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.032
MutPred		0.29		Gain of glycosylation at T13 (P = 0.1025);Gain of glycosylation at T13 (P = 0.1025);Gain of glycosylation at T13 (P = 0.1025);
MVP		0.014
MPC		0.045
ClinPred		0.064	T
GERP RS		-4.0
Varity_R		0.026
gMVP		0.042

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: rs1438441396; hg19: chr11-18158783;