chr3-9840238-G-C

Variant names:

• chr3-9840238-G-C
• rs767103943
• NM_173659.5:c.646C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_173659.5(RPUSD3):​c.646C>G​(p.Arg216Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPUSD3 NM_173659.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

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]

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPUSD3	NM_173659.5	MANE Select	c.646C>G	p.Arg216Gly	missense	Exon 7 of 9	NP_775930.3
	RPUSD3	NM_001142547.3		c.601C>G	p.Arg201Gly	missense	Exon 6 of 8	NP_001136019.2
	RPUSD3	NM_001351738.2		c.674C>G	p.Ser225Trp	missense	Exon 7 of 9	NP_001338667.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPUSD3	ENST00000383820.10	TSL:1 MANE Select	c.646C>G	p.Arg216Gly	missense	Exon 7 of 9	ENSP00000373331.6
	RPUSD3	ENST00000433535.7	TSL:1	c.601C>G	p.Arg201Gly	missense	Exon 6 of 8	ENSP00000398921.3
	RPUSD3	ENST00000427174.5	TSL:5	c.668C>G	p.Ser223Trp	missense	Exon 7 of 9	ENSP00000400397.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.3
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.041	D
Polyphen		0.85	P
Vest4		0.57
MutPred		0.70		Loss of MoRF binding (P = 0.0144)
MVP		0.63
MPC		0.66
ClinPred		0.85	D
GERP RS		3.3
PromoterAI		-0.0018	Neutral
Varity_R		0.66
gMVP		0.75
Mutation Taster		=93/7	polymorphism

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: rs767103943; hg19: chr3-9881922;