dbSNP rs1170872242: RHOT1:p.Pro337Arg (chr17-32199460-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001033566.3(RHOT1):c.1010C>G(p.Pro337Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,034 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. P337T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RHOT1
NM_001033566.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

Genes affected

RHOT1 (HGNC:21168): (ras homolog family member T1) Predicted to enable GTP binding activity and GTPase activity. Involved in cellular homeostasis; mitochondrial outer membrane permeabilization; and mitochondrion transport along microtubule. Is integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

RHOT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033566.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHOT1	NM_001033566.3	MANE Select	c.1010C>G	p.Pro337Arg	missense	Exon 13 of 20	NP_001028738.1	Q8IXI2-7
RHOT1	NM_001033568.3		c.1010C>G	p.Pro337Arg	missense	Exon 13 of 21	NP_001028740.1	Q8IXI2-3
RHOT1	NM_001288754.2		c.1010C>G	p.Pro337Arg	missense	Exon 13 of 20	NP_001275683.1	Q8IXI2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHOT1	ENST00000545287.7	TSL:5 MANE Select	c.1010C>G	p.Pro337Arg	missense	Exon 13 of 20	ENSP00000439737.2	Q8IXI2-7
RHOT1	ENST00000358365.7	TSL:1	c.1010C>G	p.Pro337Arg	missense	Exon 13 of 21	ENSP00000351132.3	Q8IXI2-3
RHOT1	ENST00000333942.10	TSL:1	c.1010C>G	p.Pro337Arg	missense	Exon 13 of 19	ENSP00000334724.6	Q8IXI2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461034

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111652

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.0

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.93

MutPred

0.81

Gain of ubiquitination at K334 (P = 0.0577)

MVP

0.85

MPC

1.6

ClinPred

1.0

GERP RS

5.7

Varity_R

0.78

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over