chr11-126203588-G-C

Position:

• chr11-126203588-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032795.3(RPUSD4):​c.964C>G​(p.Leu322Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RPUSD4 NM_032795.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.22

Genes affected

RPUSD4 (HGNC:25898): (RNA pseudouridine synthase D4) Enables mitochondrial ribosomal large subunit rRNA binding activity; pseudouridine synthase activity; and tRNA binding activity. Involved in mitochondrial tRNA pseudouridine synthesis and positive regulation of mitochondrial translation. Located in mitochondrion; nucleoplasm; and ribonucleoprotein granule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPUSD4	NM_032795.3	c.964C>G	p.Leu322Val	missense_variant	7/7	ENST00000298317.9
RPUSD4	NM_001363516.2	c.961C>G	p.Leu321Val	missense_variant	7/7
RPUSD4	NM_001144827.2	c.871C>G	p.Leu291Val	missense_variant	7/7
RPUSD4	XM_011543039.3	c.385C>G	p.Leu129Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPUSD4	ENST00000298317.9	c.964C>G	p.Leu322Val	missense_variant	7/7	1	NM_032795.3	P1
RPUSD4	ENST00000533628.5	c.871C>G	p.Leu291Val	missense_variant	7/7	1
RPUSD4	ENST00000526942.5	n.985C>G		non_coding_transcript_exon_variant	7/7	5
RPUSD4	ENST00000530903.1	n.1138C>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250644 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135588

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.69		Loss of loop (P = 0.0512);.;
MVP		0.85
MPC		0.62
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.66

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: rs571835634; hg19: chr11-126073483;