chr16-53557-G-C

Variant names:

• chr16-53557-G-C
• rs199971107
• NM_016310.5:c.30C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_016310.5(POLR3K):​c.30C>G​(p.Asn10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N10N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: POLR3K NM_016310.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 1 publications found

Genes affected

POLR3K (HGNC:14121): (RNA polymerase III subunit K) This gene encodes a small essential subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The carboxy-terminal domain of this subunit shares a high degree of sequence similarity to the carboxy-terminal domain of an RNA polymerase II elongation factor. This similarity in sequence is supported by functional studies showing that this subunit is required for proper pausing and termination during transcription. Pseudogenes of this gene are found on chromosomes 13 and 17.[provided by RefSeq, Jul 2010]

POLR3K Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 21

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.088583 (below the threshold of 3.09). Trascript score misZ: 0.18956 (below the threshold of 3.09). GenCC associations: The gene is linked to leukodystrophy, hypomyelinating, 21.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016310.5. 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
	POLR3K	NM_016310.5	MANE Select	c.30C>G	p.Asn10Lys	missense	Exon 1 of 3	NP_057394.3	Q9Y2Y1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3K	ENST00000293860.6	TSL:1 MANE Select	c.30C>G	p.Asn10Lys	missense	Exon 1 of 3	ENSP00000293860.5	Q9Y2Y1
	POLR3K	ENST00000913642.1		c.30C>G	p.Asn10Lys	missense	Exon 1 of 2	ENSP00000583701.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460774 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726680

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111686

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.11	T
PhyloP100		0.27
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Vest4		0.75
MutPred		0.73		Gain of glycosylation at N10 (P = 0.0279)
MVP		0.79
MPC		1.3
ClinPred		1.0	D
GERP RS		0.40
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.81
Mutation Taster		=53/47	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: rs199971107; hg19: chr16-103557;