16-670460-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001352287.1(RHOT2):​c.-303C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000773 in 1,604,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

RHOT2
NM_001352287.1 5_prime_UTR_premature_start_codon_gain

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.79
Variant links:
Genes affected
RHOT2 (HGNC:21169): (ras homolog family member T2) This gene encodes a member of the Rho family of GTPases. The encoded protein is localized to the outer mitochondrial membrane and plays a role in mitochondrial trafficking and fusion-fission dynamics. [provided by RefSeq, Nov 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RHOT2NM_138769.3 linkc.443C>T p.Ser148Leu missense_variant 8/19 ENST00000315082.9 NP_620124.1 Q8IXI1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RHOT2ENST00000315082.9 linkc.443C>T p.Ser148Leu missense_variant 8/191 NM_138769.3 ENSP00000321971.4 Q8IXI1-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000868
AC:
21
AN:
242022
Hom.:
0
AF XY:
0.000107
AC XY:
14
AN XY:
131144
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000184
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.0000757
AC:
110
AN:
1452694
Hom.:
0
Cov.:
33
AF XY:
0.0000692
AC XY:
50
AN XY:
722272
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000921
Gnomad4 OTH exome
AF:
0.000117
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000104
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2024The c.443C>T (p.S148L) alteration is located in exon 8 (coding exon 8) of the RHOT2 gene. This alteration results from a C to T substitution at nucleotide position 443, causing the serine (S) at amino acid position 148 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.80
D;.;D
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
5.1
H;.;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-5.8
D;.;.
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.98
MVP
0.97
MPC
0.52
ClinPred
0.99
D
GERP RS
4.1
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.94
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143933290; hg19: chr16-720460; COSMIC: COSV53468864; COSMIC: COSV53468864; API