Genetic Variant MRGPRX1:p.Leu223Leu (chr11-18934118-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001393578.1(MRGPRX1):c.667C>T(p.Leu223Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,610,844 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 59 hom., cov: 35)

Exomes 𝑓: 0.0011 ( 59 hom. )

Consequence

MRGPRX1
NM_001393578.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.572

Publications

2 publications found

Variant links:

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]

MRGPRX1 links:

ENSG00000255244 (HGNC:):

ENSG00000255244 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 11-18934118-G-A is Benign according to our data. Variant chr11-18934118-G-A is described in ClinVar as Benign. ClinVar VariationId is 718088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.572 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00977 (1480/151478) while in subpopulation AFR AF = 0.0339 (1401/41316). AF 95% confidence interval is 0.0324. There are 59 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 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.667C>T	p.Leu223Leu	synonymous	Exon 2 of 2	NP_001380507.1	Q96LB2
	MRGPRX1	NM_147199.4		c.667C>T	p.Leu223Leu	synonymous	Exon 1 of 1	NP_671732.3	Q96LB2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRGPRX1	ENST00000526914.2	TSL:3 MANE Select	c.667C>T	p.Leu223Leu	synonymous	Exon 2 of 2	ENSP00000499076.2	Q96LB2
MRGPRX1	ENST00000302797.4	TSL:6	c.667C>T	p.Leu223Leu	synonymous	Exon 1 of 1	ENSP00000305766.3	Q96LB2
ENSG00000255244	ENST00000836338.1		n.374-5187G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00976

AC:

1477

AN:

151360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00311

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00772

GnomAD2 exomes

AF:

0.00254

AC:

636

AN:

250704

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00106

AC:

1547

AN:

1459366

Hom.:

Cov.:

AF XY:

0.000921

AC XY:

669

AN XY:

725994

show subpopulations

African (AFR)

AF:

0.0372

AC:

1243

AN:

33426

American (AMR)

AF:

0.00149

AC:

AN:

44298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.000105

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000865

AC:

AN:

1110420

Other (OTH)

AF:

0.00206

AC:

124

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00977

AC:

1480

AN:

151478

Hom.:

Cov.:

AF XY:

0.00928

AC XY:

687

AN XY:

74030

show subpopulations

African (AFR)

AF:

0.0339

AC:

1401

AN:

41316

American (AMR)

AF:

0.00311

AC:

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.000210

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000192

AC:

AN:

67812

Other (OTH)

AF:

0.00764

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.0108

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.0

(source)

DANN

Benign

0.88

PhyloP100

-0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over