2-86106252-C-T

Variant names:

• chr2-86106252-C-T
• rs13393659
• NM_017952.6:c.5C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017952.6(PTCD3):​c.5C>T​(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.00751 in 1,613,754 control chromosomes in the GnomAD database, including 792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.040 (428 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (364 hom.)
• Consequence: PTCD3 NM_017952.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.99

Genes affected

PTCD3 (HGNC:24717): (pentatricopeptide repeat domain 3) Enables rRNA binding activity and ribosomal small subunit binding activity. Involved in mitochondrial translation. Located in several cellular components, including cytosol; mitochondrion; and nucleoplasm. Implicated in combined oxidative phosphorylation deficiency 51. [provided by Alliance of Genome Resources, Apr 2022]

POLR1A (HGNC:17264): (RNA polymerase I subunit A) The protein encoded by this gene is the largest subunit of the RNA polymerase I complex. The encoded protein represents the catalytic subunit of the complex, which transcribes DNA into ribosomal RNA precursors. Defects in this gene are a cause of the Cincinnati type of acrofacial dysostosis. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027564764).
• BP6: Variant 2-86106252-C-T is Benign according to our data. Variant chr2-86106252-C-T is described in ClinVar as [Benign]. Clinvar id is 1273760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD3	NM_017952.6	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 24	ENST00000254630.12	NP_060422.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD3	ENST00000254630.12	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 24	1	NM_017952.6	ENSP00000254630.7

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6045 AN: 152166 Hom.: 429 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0104 AC: 2605 AN: 251368 Hom.: 160 AF XY: 0.00766 AC XY: 1041 AN XY: 135888

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00416 AC: 6075 AN: 1461470 Hom.: 364 Cov.: 31 AF XY: 0.00363 AC XY: 2636 AN XY: 727066

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.00889

GnomAD4 genome AF: 0.0397 AC: 6045 AN: 152284 Hom.: 428 Cov.: 33 AF XY: 0.0381 AC XY: 2838 AN XY: 74472

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00809 Hom.: 100

Bravo AF: 0.0451

ESP6500AA AF: 0.131 AC: 576

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0128 AC: 1557

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 22, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0076	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.49	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.43	N;N;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.51
MPC		0.31
ClinPred		0.062	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.68

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: rs13393659; hg19: chr2-86333375;