Genetic Variant RHOQ:p.Arg72Leu (chr2-46576100-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012249.4(RHOQ):c.215G>T(p.Arg72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHOQ
NM_012249.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.88

Publications

0 publications found

Variant links:

Genes affected

RHOQ (HGNC:17736): (ras homolog family member Q) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein is an important signalling protein for sarcomere assembly and has been shown to play a significant role in the exocytosis of the solute carrier family 2, facilitated glucose transporter member 4 and other proteins, possibly acting as the signal that turns on the membrane fusion machinery. Three related pseudogene have been identified on chromosomes 2 and 14. [provided by RefSeq, Aug 2011]

RHOQ links:

RHOQ-AS1 (HGNC:40816): (RHOQ antisense RNA 1)

RHOQ-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOQ	NM_012249.4 link	c.215G>T	p.Arg72Leu	missense_variant	Exon 3 of 5	ENST00000238738.9	NP_036381.2	P17081V9HWD0
RHOQ	XM_011532726.3 link	c.215G>T	p.Arg72Leu	missense_variant	Exon 3 of 6		XP_011531028.1
RHOQ-AS1	NR_104182.1 link	n.204+3935C>A		intron_variant	Intron 1 of 1
RHOQ	XM_005264229.3 link	c.202-4828G>T		intron_variant	Intron 2 of 2		XP_005264286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOQ	ENST00000238738.9 link	c.215G>T	p.Arg72Leu	missense_variant	Exon 3 of 5	1	NM_012249.4	ENSP00000238738.4		P17081

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453318

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723626

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32578

American (AMR)

AF:

0.00

AC:

AN:

42068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00

AC:

AN:

85628

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109012

Other (OTH)

AF:

0.00

AC:

AN:

59856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.055

MutationAssessor

Uncertain

2.7

PhyloP100

6.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

0.095

Vest4

0.78

MutPred

0.61

Loss of disorder (P = 0.0336);

MVP

0.89

MPC

1.0

ClinPred

0.99

GERP RS

5.4

Varity_R

0.86

gMVP

0.86

Mutation Taster

=39/61

disease causing

(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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2-46576100-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over