chr17-32211132-T-C

Position:

• chr17-32211132-T-C

Variant summary

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

The NM_001033566.3(RHOT1):​c.1756T>C​(p.Cys586Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOT1 NM_001033566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOT1	NM_001033566.3	c.1756T>C	p.Cys586Arg	missense_variant	19/20	ENST00000545287.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOT1	ENST00000545287.7	c.1756T>C	p.Cys586Arg	missense_variant	19/20	5	NM_001033566.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

May 14, 2024

The c.1852T>C (p.C618R) alteration is located in exon 20 (coding exon 20) of the RHOT1 gene. This alteration results from a T to C substitution at nucleotide position 1852, causing the cysteine (C) at amino acid position 618 to be replaced by an arginine (R). 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
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Benign	0.91
DEOGEN2	Benign	0.024	.;.;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.81
MVP		0.71
MPC		1.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.84

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: rs367846455; hg19: chr17-30538151;