NM_138769.3:c.280C>G

Variant names:

• chr16-670126-C-G
• rs755243388
• NM_138769.3:c.280C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138769.3(RHOT2):​c.280C>G​(p.Arg94Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RHOT2 NM_138769.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31664053).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138769.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOT2	NM_138769.3	MANE Select	c.280C>G	p.Arg94Gly	missense	Exon 6 of 19	NP_620124.1	Q8IXI1-1
	RHOT2	NM_001352280.2		c.-25C>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 19	NP_001339209.1
	RHOT2	NM_001352281.2		c.-25C>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 19	NP_001339210.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOT2	ENST00000315082.9	TSL:1 MANE Select	c.280C>G	p.Arg94Gly	missense	Exon 6 of 19	ENSP00000321971.4	Q8IXI1-1
	RHOT2	ENST00000697194.1		c.280C>G	p.Arg94Gly	missense	Exon 6 of 19	ENSP00000513180.1	A0A8V8TM48
	RHOT2	ENST00000958324.1		c.280C>G	p.Arg94Gly	missense	Exon 6 of 19	ENSP00000628383.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410866 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697530

African (AFR) AF: 0.00 AC: 0 AN: 31008

American (AMR) AF: 0.00 AC: 0 AN: 34002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 80178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088150

Other (OTH) AF: 0.00 AC: 0 AN: 57978

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.28
Sift	Benign	0.13	T
Sift4G	Benign	0.34	T
Polyphen		0.022	B
Vest4		0.37
MutPred		0.49		Loss of stability (P = 0.0506)
MVP		0.88
MPC		0.19
ClinPred		0.24	T
GERP RS		3.0
Varity_R		0.25
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs755243388; hg19: chr16-720126;