3-58316930-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001348712.2(HTD2):c.-238G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HTD2
NM_001348712.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.95

Variant links:

Genes affected

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]

HTD2 links:

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]

RPP14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3767124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HTD2	NM_001348712.2 link	c.-238G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 5	ENST00000461393.7	NP_001335641.1
RPP14	NM_007042.6 link	c.255G>T	p.Leu85Phe	missense_variant	Exon 5 of 6	ENST00000295959.10	NP_008973.1
HTD2	NM_001348712.2 link	c.-238G>T		5_prime_UTR_variant	Exon 4 of 5	ENST00000461393.7	NP_001335641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTD2	ENST00000461393 link	c.-238G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 5	1	NM_001348712.2	ENSP00000484277.1	P86397
RPP14	ENST00000295959.10 link	c.255G>T	p.Leu85Phe	missense_variant	Exon 5 of 6	1	NM_007042.6	ENSP00000295959.5	O95059
HTD2	ENST00000461393 link	c.-238G>T		5_prime_UTR_variant	Exon 4 of 5	1	NM_001348712.2	ENSP00000484277.1	P86397

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251134

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000870

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000151

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000291

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.255G>T (p.L85F) alteration is located in exon 5 (coding exon 4) of the RPP14 gene. This alteration results from a G to T substitution at nucleotide position 255, causing the leucine (L) at amino acid position 85 to be replaced by a phenylalanine (F). 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

0.21

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

.;.;D

M_CAP

Benign

0.0047

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.065

T;T;T

Sift4G

Uncertain

0.012

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.70

MutPred

0.83

Gain of methylation at K84 (P = 0.0283);Gain of methylation at K84 (P = 0.0283);Gain of methylation at K84 (P = 0.0283);

MVP

0.41

MPC

0.92

ClinPred

0.31

GERP RS

1.6

Varity_R

0.35

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over