3-58310340-C-T

Variant names:

• chr3-58310340-C-T
• NM_007042.6:c.11C>T

Variant summary

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

The NM_007042.6(RPP14):​c.11C>T​(p.Pro4Leu) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPP14 NM_007042.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.468

Genes affected

RPP14 (HGNC:30327): (ribonuclease P/MRP subunit p14) This gene encodes a subunit of ribonuclease P and has 3' to 5' exoribonuclease activity. Transcripts for this gene are bicistronic and include a conserved downstream open reading frame for the hydroxyacyl-thioester dehydratase type 2 (HTD2) gene. [provided by RefSeq, May 2017]

HTD2 (HGNC:53111): (hydroxyacyl-thioester dehydratase type 2) This gene encodes a protein that localizes to the mitochondria and can function as a 3-hydroxyacyl thioester dehydratase. This gene is located just downstream of the gene for ribonuclease P/MRP subunit p14 (RPP14) in a genomic context that is conserved among animals. The upstream RPP14 gene is thought to be co-transcribed with this gene, and bicistronic transcripts may include open reading frames for both proteins. [provided by RefSeq, May 2017]

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=0.07353914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPP14	NM_007042.6	c.11C>T	p.Pro4Leu	missense_variant	Exon 2 of 6	ENST00000295959.10	NP_008973.1
HTD2	NM_001348712.2	c.-415-167C>T		intron_variant	Intron 1 of 4	ENST00000461393.7	NP_001335641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPP14	ENST00000295959.10	c.11C>T	p.Pro4Leu	missense_variant	Exon 2 of 6	1	NM_007042.6	ENSP00000295959.5
HTD2	ENST00000461393.7	c.-415-167C>T		intron_variant	Intron 1 of 4	1	NM_001348712.2	ENSP00000484277.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>T (p.P4L) alteration is located in exon 2 (coding exon 1) of the RPP14 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a leucine (L). 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	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0087	T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	.;.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.088
MutPred		0.40		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);
MVP		0.15
MPC		0.25
ClinPred		0.27	T
GERP RS		3.5
Varity_R		0.073
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-58296067;