NM_001393578.1:c.578G>T

Variant names:

• chr11-18934207-C-A
• rs140922847
• NM_001393578.1:c.578G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001393578.1(MRGPRX1):​c.578G>T​(p.Gly193Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,607,740 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G193G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (9 hom., cov: 35)
  • Exomes 𝑓: 0.0018 (119 hom.)
• Consequence: MRGPRX1 NM_001393578.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.748
• Publications: 9 publications found

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]

ENSG00000255244 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075779557).
• BP6: Variant 11-18934207-C-A is Benign according to our data. Variant chr11-18934207-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2641674.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393578.1. 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
	MRGPRX1	NM_001393578.1	MANE Select	c.578G>T	p.Gly193Val	missense	Exon 2 of 2	NP_001380507.1	Q96LB2
	MRGPRX1	NM_147199.4		c.578G>T	p.Gly193Val	missense	Exon 1 of 1	NP_671732.3	Q96LB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRGPRX1	ENST00000526914.2	TSL:3 MANE Select	c.578G>T	p.Gly193Val	missense	Exon 2 of 2	ENSP00000499076.2	Q96LB2
	MRGPRX1	ENST00000302797.4	TSL:6	c.578G>T	p.Gly193Val	missense	Exon 1 of 1	ENSP00000305766.3	Q96LB2
	ENSG00000255244	ENST00000836338.1		n.374-5098C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 338 AN: 150850 Hom.: 9 Cov.: 35

Gnomad AFR AF: 0.000754

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00534

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00296

Gnomad OTH AF: 0.00532

GnomAD2 exomes AF: 0.000576 AC: 144 AN: 250166 AF XY: 0.000458

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000707

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.00177 AC: 2573 AN: 1456772 Hom.: 119 Cov.: 37 AF XY: 0.00180 AC XY: 1305 AN XY: 724778

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000359 AC: 12 AN: 33446

American (AMR) AF: 0.00368 AC: 163 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86036

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53332

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5754

European-Non Finnish (NFE) AF: 0.00202 AC: 2235 AN: 1107938

Other (OTH) AF: 0.00202 AC: 122 AN: 60250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00224 AC: 338 AN: 150968 Hom.: 9 Cov.: 35 AF XY: 0.00222 AC XY: 164 AN XY: 73762

African (AFR) AF: 0.000752 AC: 31 AN: 41232

American (AMR) AF: 0.00533 AC: 80 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10516

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00296 AC: 200 AN: 67646

Other (OTH) AF: 0.00526 AC: 11 AN: 2090

Alfa AF: 0.00147 Hom.: 4

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.8
DANN	Benign	0.62
DEOGEN2	Benign	0.049	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		-0.75
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.050
Sift	Benign	0.29	T
Sift4G	Benign	0.94	T
Polyphen		0.051	B
Vest4		0.14
MVP		0.24
MPC		0.043
ClinPred		0.034	T
GERP RS		-4.6
Varity_R		0.16
gMVP		0.20
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs140922847; hg19: chr11-18955754; COSMIC: COSV57106235; COSMIC: COSV57106235;