Genetic Variant RHOT1:c.1739+528G>A (chr17-32208837-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001033566.3(RHOT1):c.1739+528G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 155,640 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.032 ( 128 hom., cov: 32)

Exomes 𝑓: 0.039 ( 3 hom. )

Consequence

RHOT1
NM_001033566.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.960

Publications

5 publications found

Variant links:

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]

RHOT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0317 (4829/152122) while in subpopulation NFE AF = 0.0463 (3146/67988). AF 95% confidence interval is 0.0449. There are 128 homozygotes in GnomAd4. There are 2408 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4829 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RHOT1	NM_001033566.3	MANE Select	c.1739+528G>A	intron	N/A	NP_001028738.1
RHOT1	NM_001033568.3		c.1740-513G>A	intron	N/A	NP_001028740.1
RHOT1	NM_001288754.2		c.1740-513G>A	intron	N/A	NP_001275683.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RHOT1	ENST00000545287.7	TSL:5 MANE Select	c.1739+528G>A	intron	N/A	ENSP00000439737.2
RHOT1	ENST00000358365.7	TSL:1	c.1740-513G>A	intron	N/A	ENSP00000351132.3
RHOT1	ENST00000333942.10	TSL:1	c.1739+528G>A	intron	N/A	ENSP00000334724.6

Frequencies

GnomAD3 genomes

AF:

0.0318

AC:

4830

AN:

152004

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00778

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0150

Gnomad FIN

AF:

0.0783

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0463

Gnomad OTH

AF:

0.0206

GnomAD4 exome

AF:

0.0387

AC:

136

AN:

3518

Hom.:

Cov.:

AF XY:

0.0380

AC XY:

AN XY:

1870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0194

AC:

AN:

774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0118

AC:

AN:

338

European-Finnish (FIN)

AF:

0.0938

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0501

AC:

106

AN:

2116

Other (OTH)

AF:

0.0606

AC:

AN:

132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0317

AC:

4829

AN:

152122

Hom.:

128

Cov.:

AF XY:

0.0324

AC XY:

2408

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00775

AC:

322

AN:

41532

American (AMR)

AF:

0.0168

AC:

257

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0150

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0783

AC:

826

AN:

10552

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0463

AC:

3146

AN:

67988

Other (OTH)

AF:

0.0204

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

250

500

751

1001

1251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0392

Hom.:

237

Bravo

AF:

0.0267

Asia WGS

AF:

0.00578

AC:

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.96

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over