10-77975513-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007055.4(POLR3A):c.*1965A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,190 control chromosomes in the GnomAD database, including 5,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5129 hom., cov: 32)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: POLR3A NM_007055.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-77975513-T-C is Benign according to our data. Variant chr10-77975513-T-C is described in ClinVar as [Benign]. Clinvar id is 300986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR3A	NM_007055.4	c.*1965A>G		3_prime_UTR_variant	31/31	ENST00000372371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR3A	ENST00000372371.8	c.*1965A>G		3_prime_UTR_variant	31/31	1	NM_007055.4	P1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37450 AN: 151998 Hom.: 5112 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.216 AC: 16 AN: 74 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 10 AN XY: 40

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.247 AC: 37513 AN: 152116 Hom.: 5129 Cov.: 32 AF XY: 0.248 AC XY: 18433 AN XY: 74366

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.515

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.247

Alfa AF: 0.176 Hom.: 765

Bravo AF: 0.255

Asia WGS AF: 0.428 AC: 1487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.2
Dann	Benign	0.39

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: rs2241546; hg19: chr10-79735271;