3-9840277-C-A

Variant names:

• chr3-9840277-C-A
• rs745877910
• NM_173659.5:c.607G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173659.5(RPUSD3):​c.607G>T​(p.Asp203Tyr) 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 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. D203H) has been classified as Uncertain significance.

• 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: 1.20
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33793837).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPUSD3	NM_173659.5	MANE Select	c.607G>T	p.Asp203Tyr	missense	Exon 7 of 9	NP_775930.3	Q6P087-5
	RPUSD3	NM_001142547.3		c.562G>T	p.Asp188Tyr	missense	Exon 6 of 8	NP_001136019.2	Q6P087-6
	RPUSD3	NM_001351738.2		c.635G>T	p.Gly212Val	missense	Exon 7 of 9	NP_001338667.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPUSD3	ENST00000383820.10	TSL:1 MANE Select	c.607G>T	p.Asp203Tyr	missense	Exon 7 of 9	ENSP00000373331.6	Q6P087-5
	RPUSD3	ENST00000433535.7	TSL:1	c.562G>T	p.Asp188Tyr	missense	Exon 6 of 8	ENSP00000398921.3	Q6P087-6
	RPUSD3	ENST00000923702.1		c.733G>T	p.Asp245Tyr	missense	Exon 8 of 10	ENSP00000593761.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251480 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0094	T
Eigen	Benign	0.099
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.62		Gain of MoRF binding (P = 0.0385)
MVP		0.57
MPC		0.58
ClinPred		0.86	D
GERP RS		3.3
PromoterAI		0.011	Neutral
Varity_R		0.14
gMVP		0.71
Mutation Taster		=87/13	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: rs745877910; hg19: chr3-9881961;