3-9838027-G-A

Variant names:

• chr3-9838027-G-A
• rs187102720
• NM_173659.5:c.1021C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_173659.5(RPUSD3):​c.1021C>T​(p.Arg341Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,572,398 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: RPUSD3 NM_173659.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.315

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011306614).
• BP6: Variant 3-9838027-G-A is Benign according to our data. Variant chr3-9838027-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2354046.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPUSD3	NM_173659.5	c.1021C>T	p.Arg341Cys	missense_variant	Exon 9 of 9	ENST00000383820.10	NP_775930.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPUSD3	ENST00000383820.10	c.1021C>T	p.Arg341Cys	missense_variant	Exon 9 of 9	1	NM_173659.5	ENSP00000373331.6

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000933 AC: 17 AN: 182274 Hom.: 0 AF XY: 0.0000927 AC XY: 9 AN XY: 97098

Gnomad AFR exome AF: 0.000702

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000783

Gnomad FIN exome AF: 0.000179

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000410

GnomAD4 exome AF: 0.0000591 AC: 84 AN: 1420138 Hom.: 1 Cov.: 31 AF XY: 0.0000612 AC XY: 43 AN XY: 702232

Gnomad4 AFR exome AF: 0.000577

Gnomad4 AMR exome AF: 0.0000267

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000524

Gnomad4 SAS exome AF: 0.0000978

Gnomad4 FIN exome AF: 0.000138

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.000408

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74458

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000505 AC: 6

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 14, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.8
DANN	Benign	0.78
DEOGEN2	Benign	0.027	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.019
Sift	Benign	0.17	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.030	B;B
Vest4		0.092
MVP		0.17
MPC		0.20
ClinPred		0.0082	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs187102720; hg19: chr3-9879711; COSMIC: COSV59615284; COSMIC: COSV59615284;