17-32192231-C-T

Variant names:

• chr17-32192231-C-T
• rs781771828
• NM_001033566.3:c.571C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001033566.3(RHOT1):​c.571C>T​(p.Arg191Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,563,014 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RHOT1 NM_001033566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70
• Publications: 5 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033566.3. 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
	RHOT1	NM_001033566.3	MANE Select	c.571C>T	p.Arg191Cys	missense	Exon 9 of 20	NP_001028738.1	Q8IXI2-7
	RHOT1	NM_001033568.3		c.571C>T	p.Arg191Cys	missense	Exon 9 of 21	NP_001028740.1	Q8IXI2-3
	RHOT1	NM_001288754.2		c.571C>T	p.Arg191Cys	missense	Exon 9 of 20	NP_001275683.1	Q8IXI2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOT1	ENST00000545287.7	TSL:5 MANE Select	c.571C>T	p.Arg191Cys	missense	Exon 9 of 20	ENSP00000439737.2	Q8IXI2-7
	RHOT1	ENST00000358365.7	TSL:1	c.571C>T	p.Arg191Cys	missense	Exon 9 of 21	ENSP00000351132.3	Q8IXI2-3
	RHOT1	ENST00000333942.10	TSL:1	c.571C>T	p.Arg191Cys	missense	Exon 9 of 19	ENSP00000334724.6	Q8IXI2-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151818 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000175 AC: 4 AN: 228022 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000113 AC: 16 AN: 1411196 Hom.: 0 Cov.: 26 AF XY: 0.00000995 AC XY: 7 AN XY: 703648

African (AFR) AF: 0.00 AC: 0 AN: 31222

American (AMR) AF: 0.00 AC: 0 AN: 36536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 79778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1082298

Other (OTH) AF: 0.00 AC: 0 AN: 58480

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151818 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.81		Gain of sheet (P = 0.0125)
MVP		0.88
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.87
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs781771828; hg19: chr17-30519250; COSMIC: COSV61714783;