chr16-670293-G-A

Position:

• chr16-670293-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138769.3(RHOT2):​c.374G>A​(p.Gly125Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHOT2 NM_138769.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21220389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOT2	NM_138769.3	c.374G>A	p.Gly125Glu	missense_variant	7/19	ENST00000315082.9	NP_620124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOT2	ENST00000315082.9	c.374G>A	p.Gly125Glu	missense_variant	7/19	1	NM_138769.3	ENSP00000321971.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460490 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726520

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.374G>A (p.G125E) alteration is located in exon 7 (coding exon 7) of the RHOT2 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the glycine (G) at amino acid position 125 to be replaced by a glutamic acid (E). 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	Benign	0.12
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.76
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.025	N;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;.;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.77	T;T;T
Polyphen		0.36	B;.;.
Vest4		0.62
MutPred		0.33		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);.;
MVP		0.83
MPC		0.22
ClinPred		0.63	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.59

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: rs2038698328; hg19: chr16-720293;