Genetic Variant RHOQ:p.Met9Thr (chr2-46543072-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012249.4(RHOQ):c.26T>C(p.Met9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. M9K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHOQ
NM_012249.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.730

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13573894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOQ	NM_012249.4 link	c.26T>C	p.Met9Thr	missense_variant	Exon 1 of 5	ENST00000238738.9	NP_036381.2	P17081V9HWD0
RHOQ	XM_011532726.3 link	c.26T>C	p.Met9Thr	missense_variant	Exon 1 of 6		XP_011531028.1
RHOQ	XM_005264229.3 link	c.26T>C	p.Met9Thr	missense_variant	Exon 1 of 3		XP_005264286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RHOQ	ENST00000238738.9 link	c.26T>C	p.Met9Thr	missense_variant	Exon 1 of 5	1	NM_012249.4	ENSP00000238738.4	P17081
RHOQ	ENST00000432183.5 link	n.26T>C		non_coding_transcript_exon_variant	Exon 1 of 3	5		ENSP00000393140.1	F8WET9
RHOQ	ENST00000465198.1 link	n.155+1112T>C		intron_variant	Intron 1 of 1	3
RHOQ	ENST00000489471.5 link	n.-77T>C		upstream_gene_variant		5		ENSP00000428624.1	H0YB40

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723000

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32416

American (AMR)

AF:

0.00

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

38606

South Asian (SAS)

AF:

0.00

AC:

AN:

85476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108892

Other (OTH)

AF:

0.00

AC:

AN:

59992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.12

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.88

PhyloP100

0.73

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

1.6

REVEL

Benign

0.064

Sift

Benign

0.92

Sift4G

Benign

0.41

Polyphen

0.099

Vest4

0.34

MutPred

0.41

Loss of ubiquitination at K11 (P = 0.0952);

MVP

0.50

MPC

1.5

ClinPred

0.81

GERP RS

1.1

PromoterAI

0.19

Neutral

(source)

Varity_R

0.50

gMVP

0.82

Mutation Taster

=33/67

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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2-46543072-T-C

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