Genetic Variant POLR3A:c.1431+626A>G (chr10-78016949-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007055.4(POLR3A):c.1431+626A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 152,130 control chromosomes in the GnomAD database, including 283 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 0.032 ( 283 hom., cov: 31)

Consequence

POLR3A
NM_007055.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0400

Publications

1 publications found

Variant links:

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

POLR3A links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4 link	c.1431+626A>G		intron_variant	Intron 10 of 30	ENST00000372371.8	NP_008986.2	O14802

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8 link	c.1431+626A>G		intron_variant	Intron 10 of 30	1	NM_007055.4	ENSP00000361446.3		O14802

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4825

AN:

152012

Hom.:

283

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0317

AC:

4829

AN:

152130

Hom.:

283

Cov.:

AF XY:

0.0310

AC XY:

2305

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.111

AC:

4600

AN:

41464

American (AMR)

AF:

0.0102

AC:

156

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68020

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

212

423

635

846

1058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0301

Hom.:

Bravo

AF:

0.0369

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.9

(source)

DANN

Benign

0.28

PhyloP100

0.040

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over