3-9840238-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_173659.5(RPUSD3):c.646C>T(p.Arg216Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RPUSD3
NM_173659.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.28

Publications

0 publications found

Variant links:

Genes affected

RPUSD3 (HGNC:28437): (RNA pseudouridine synthase D3) This gene encodes a protein that functions in the assembly of the mitochondrial ribosome by adding a pseudouridine group to 16S rRNA. Loss of this gene results in causes defects in mitochondrial protein production. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

RPUSD3 links:

TTLL3 (HGNC:24483): (tubulin tyrosine ligase like 3) Enables protein-glycine ligase activity. Predicted to be involved in axoneme assembly and flagellated sperm motility. Predicted to be located in axoneme; microtubule cytoskeleton; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

TTLL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-9840238-G-A is Pathogenic according to our data. Variant chr3-9840238-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225035.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173659.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPUSD3	NM_173659.5	MANE Select	c.646C>T	p.Arg216Cys	missense	Exon 7 of 9	NP_775930.3
RPUSD3	NM_001142547.3		c.601C>T	p.Arg201Cys	missense	Exon 6 of 8	NP_001136019.2
RPUSD3	NM_001351738.2		c.674C>T	p.Ser225Leu	missense	Exon 7 of 9	NP_001338667.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPUSD3	ENST00000383820.10	TSL:1 MANE Select	c.646C>T	p.Arg216Cys	missense	Exon 7 of 9	ENSP00000373331.6
RPUSD3	ENST00000433535.7	TSL:1	c.601C>T	p.Arg201Cys	missense	Exon 6 of 8	ENSP00000398921.3
RPUSD3	ENST00000427174.5	TSL:5	c.668C>T	p.Ser223Leu	missense	Exon 7 of 9	ENSP00000400397.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251442

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Overall WES conclusion for patient, including all identified alterations: POSSIBLY POSITIVE: Alteration(s) of Uncertain Clinical Significance Detected (Novel Gene)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.080

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.1

PhyloP100

1.3

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.55

MutPred

0.74

Loss of MoRF binding (P = 0.0068)

MVP

0.61

MPC

0.73

ClinPred

0.80

GERP RS

3.3

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.57

gMVP

0.69

Mutation Taster

=91/9

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over