rs4979935

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: Orphanet, Illumina
• POLR3A-related disorder

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 VariationId 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.

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.*1763G>A		3_prime_UTR	Exon 31 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.*1763G>A		3_prime_UTR	Exon 31 of 31	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.*1763G>A		3_prime_UTR	Exon 30 of 30	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.*1763G>A		3_prime_UTR	Exon 30 of 30	ENSP00000513898.1	A0A8V8TNX3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;