rs8466

Variant names:

• chr16-47354-A-G
• rs8466
• NM_016310.5:c.*76T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016310.5(POLR3K):​c.*76T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,543,572 control chromosomes in the GnomAD database, including 22,534 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3770 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18764 hom.)
• Consequence: POLR3K NM_016310.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 21 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

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.*76T>C		3_prime_UTR	Exon 3 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.*76T>C		3_prime_UTR	Exon 3 of 3	ENSP00000293860.5	Q9Y2Y1
	POLR3K	ENST00000913642.1		c.*76T>C		3_prime_UTR	Exon 2 of 2	ENSP00000583701.1
	POLR3K	ENST00000481810.1	TSL:2	n.789T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30311 AN: 152016 Hom.: 3756 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.155 AC: 216221 AN: 1391438 Hom.: 18764 Cov.: 25 AF XY: 0.155 AC XY: 106814 AN XY: 689674

African (AFR) AF: 0.343 AC: 10821 AN: 31548

American (AMR) AF: 0.119 AC: 4871 AN: 40838

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6170 AN: 24134

East Asian (EAS) AF: 0.000188 AC: 7 AN: 37154

South Asian (SAS) AF: 0.111 AC: 9083 AN: 81514

European-Finnish (FIN) AF: 0.0924 AC: 4409 AN: 47706

Middle Eastern (MID) AF: 0.253 AC: 1309 AN: 5176

European-Non Finnish (NFE) AF: 0.159 AC: 169814 AN: 1066406

Other (OTH) AF: 0.171 AC: 9737 AN: 56962

GnomAD4 genome AF: 0.200 AC: 30369 AN: 152134 Hom.: 3770 Cov.: 32 AF XY: 0.194 AC XY: 14435 AN XY: 74400

African (AFR) AF: 0.336 AC: 13937 AN: 41452

American (AMR) AF: 0.165 AC: 2524 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0961 AC: 464 AN: 4828

European-Finnish (FIN) AF: 0.0936 AC: 991 AN: 10592

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10833 AN: 68002

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.175 Hom.: 1399

Bravo AF: 0.212

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.49
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs8466; hg19: chr16-97354; COSMIC: COSV53452622;