11-126203561-C-A

Variant names:

• chr11-126203561-C-A
• rs140615422
• NM_032795.3:c.991G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032795.3(RPUSD4):​c.991G>T​(p.Ala331Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPUSD4 NM_032795.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1431664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPUSD4	NM_032795.3	c.991G>T	p.Ala331Ser	missense_variant	Exon 7 of 7	ENST00000298317.9	NP_116184.2
RPUSD4	NM_001363516.2	c.988G>T	p.Ala330Ser	missense_variant	Exon 7 of 7		NP_001350445.1
RPUSD4	NM_001144827.2	c.898G>T	p.Ala300Ser	missense_variant	Exon 7 of 7		NP_001138299.1
RPUSD4	XM_011543039.3	c.412G>T	p.Ala138Ser	missense_variant	Exon 5 of 5		XP_011541341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPUSD4	ENST00000298317.9	c.991G>T	p.Ala331Ser	missense_variant	Exon 7 of 7	1	NM_032795.3	ENSP00000298317.4
RPUSD4	ENST00000533628.5	c.898G>T	p.Ala300Ser	missense_variant	Exon 7 of 7	1		ENSP00000433065.1
RPUSD4	ENST00000526942.5	n.1012G>T		non_coding_transcript_exon_variant	Exon 7 of 7	5
RPUSD4	ENST00000530903.1	n.1165G>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251124 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135774

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.991G>T (p.A331S) alteration is located in exon 7 (coding exon 7) of the RPUSD4 gene. This alteration results from a G to T substitution at nucleotide position 991, causing the alanine (A) at amino acid position 331 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.00020	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.37	N;N
REVEL	Benign	0.072
Sift	Benign	0.39	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.022	B;.
Vest4		0.22
MVP		0.35
MPC		0.14
ClinPred		0.20	T
GERP RS		3.3
Varity_R		0.068
gMVP		0.29

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: rs140615422; hg19: chr11-126073456;