NM_007055.4:c.*1763G>A

Variant names:

• chr10-77975715-C-T
• rs4979935
• NM_007055.4:c.*1763G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007055.4(POLR3A):​c.*1763G>A 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 152,228 control chromosomes in the GnomAD database, including 2,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2094 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: POLR3A NM_007055.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05
• Publications: 2 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: Illumina, Orphanet
• Wiedemann-Rautenstrauch syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-77975715-C-T is Benign according to our data. Variant chr10-77975715-C-T is described in ClinVar as [Benign]. Clinvar id is 300999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.*1763G>A		3_prime_UTR_variant	Exon 31 of 31	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.*1763G>A		3_prime_UTR_variant	Exon 31 of 31	1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24334 AN: 152044 Hom.: 2096 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.121 AC: 8 AN: 66 Hom.: 1 Cov.: 0 AF XY: 0.125 AC XY: 7 AN XY: 56

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 2 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.107 AC: 6 AN: 56

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.160 AC: 24338 AN: 152162 Hom.: 2094 Cov.: 32 AF XY: 0.158 AC XY: 11770 AN XY: 74392

African (AFR) AF: 0.125 AC: 5188 AN: 41512

American (AMR) AF: 0.150 AC: 2296 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3472

East Asian (EAS) AF: 0.274 AC: 1415 AN: 5166

South Asian (SAS) AF: 0.148 AC: 713 AN: 4820

European-Finnish (FIN) AF: 0.147 AC: 1559 AN: 10590

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11712 AN: 67998

Other (OTH) AF: 0.172 AC: 364 AN: 2112

Alfa AF: 0.170 Hom.: 9615

Bravo AF: 0.162

Asia WGS AF: 0.197 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.098
DANN	Benign	0.61
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs4979935; hg19: chr10-79735473;