rs41274610

Variant names:

• chr10-78021981-G-A
• rs41274610
• NM_007055.4:c.927C>T
• POLR3A p.Asp309Asp

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_007055.4(POLR3A):​c.927C>T​(p.Asp309Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,614,146 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (22 hom.)
• Consequence: POLR3A NM_007055.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.31
• Publications: 1 publications found

Genes affected

POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

POLR3A Gene-Disease associations (from GenCC):

• odontoleukodystrophy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• POLR3A-related disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Wiedemann-Rautenstrauch syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor-ataxia-central hypomyelination syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-78021981-G-A is Benign according to our data. Variant chr10-78021981-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211931.
• BP7: Synonymous conserved (PhyloP=3.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00284 (433/152260) while in subpopulation NFE AF = 0.00504 (343/68018). AF 95% confidence interval is 0.0046. There are 3 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007055.4. 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
	POLR3A	NM_007055.4	MANE Select	c.927C>T	p.Asp309Asp	synonymous	Exon 7 of 31	NP_008986.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3A	ENST00000372371.8	TSL:1 MANE Select	c.927C>T	p.Asp309Asp	synonymous	Exon 7 of 31	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.927C>T	p.Asp309Asp	synonymous	Exon 7 of 30	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.927C>T	p.Asp309Asp	synonymous	Exon 7 of 30	ENSP00000513898.1	A0A8V8TNX3

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00255 AC: 642 AN: 251456 AF XY: 0.00274

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00429

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00443 AC: 6478 AN: 1461886 Hom.: 22 Cov.: 33 AF XY: 0.00438 AC XY: 3186 AN XY: 727240

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.000636 AC: 34 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00544 AC: 6053 AN: 1112008

Other (OTH) AF: 0.00384 AC: 232 AN: 60396

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74458

African (AFR) AF: 0.00123 AC: 51 AN: 41552

American (AMR) AF: 0.00190 AC: 29 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00504 AC: 343 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00316

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (1)
-	-	1	POLR3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41274610;

hg19: chr10-79781739;