2-86106264-C-G

Variant names:

• chr2-86106264-C-G
• rs201067869
• NM_017952.6:c.17C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017952.6(PTCD3):​c.17C>G​(p.Ala6Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCD3 NM_017952.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315
• Publications: 0 publications found

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]

POLR1A Gene-Disease associations (from GenCC):

• acrofacial dysostosis Cincinnati type

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• leukodystrophy, hypomyelinating, 27

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07191002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017952.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCD3	NM_017952.6	MANE Select	c.17C>G	p.Ala6Gly	missense	Exon 1 of 24	NP_060422.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCD3	ENST00000254630.12	TSL:1 MANE Select	c.17C>G	p.Ala6Gly	missense	Exon 1 of 24	ENSP00000254630.7	Q96EY7-1
	PTCD3	ENST00000898160.1		c.17C>G	p.Ala6Gly	missense	Exon 1 of 24	ENSP00000568219.1
	PTCD3	ENST00000898158.1		c.17C>G	p.Ala6Gly	missense	Exon 1 of 24	ENSP00000568217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.3
DANN	Benign	0.47
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.32
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.027
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.30		Loss of helix (P = 0.0167)
MVP		0.088
MPC		0.052
ClinPred		0.12	T
GERP RS		-0.36
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.28
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs201067869; hg19: chr2-86333387;