rs1139897

Positions:

• chr16-670986-G-A
• chr16-670986-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138769.3(RHOT2):​c.734G>A​(p.Arg245Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,578,344 control chromosomes in the GnomAD database, including 60,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (5305 hom., cov: 32)
  • Exomes 𝑓: 0.26 (55248 hom.)
• Consequence: RHOT2 NM_138769.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0537154E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOT2	NM_138769.3	c.734G>A	p.Arg245Gln	missense_variant	10/19	ENST00000315082.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOT2	ENST00000315082.9	c.734G>A	p.Arg245Gln	missense_variant	10/19	1	NM_138769.3	P4

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34107 AN: 151990 Hom.: 5301 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.329 AC: 72526 AN: 220382 Hom.: 14778 AF XY: 0.327 AC XY: 39208 AN XY: 119864

Gnomad AFR exome AF: 0.0632

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.685

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.258 AC: 368530 AN: 1426236 Hom.: 55248 Cov.: 35 AF XY: 0.262 AC XY: 185041 AN XY: 706218

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.465

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.684

Gnomad4 SAS exome AF: 0.408

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.224 AC: 34123 AN: 152108 Hom.: 5305 Cov.: 32 AF XY: 0.237 AC XY: 17607 AN XY: 74346

Gnomad4 AFR AF: 0.0683

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.703

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.226

Gnomad4 OTH AF: 0.219

Alfa AF: 0.224 Hom.: 5875

Bravo AF: 0.214

TwinsUK AF: 0.229 AC: 849

ALSPAC AF: 0.217 AC: 837

ESP6500AA AF: 0.0673 AC: 294

ESP6500EA AF: 0.224 AC: 1920

ExAC AF: 0.309 AC: 37062

Asia WGS AF: 0.497 AC: 1723 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;T
MetaRNN	Benign	0.000031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	4.0e-10	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.056
Sift	Benign	0.056	T;.
Sift4G	Benign	0.080	T;D
Polyphen		0.027	B;.
Vest4		0.052
MPC		0.13
ClinPred		0.019	T
GERP RS		2.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Varity_R		0.081
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs1139897; hg19: chr16-720986; COSMIC: COSV53466230; COSMIC: COSV53466230;