chr10-77980162-C-T

Position:

chr10-77980162-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_007055.4(POLR3A):c.4003G>A(p.Gly1335Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

POLR3A
NM_007055.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.14

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR3A. . Gene score misZ 2.3065 (greater than the threshold 3.09). Trascript score misZ 3.6654 (greater than threshold 3.09). GenCC has associacion of gene with leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome, Wiedemann-Rautenstrauch syndrome, hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome, tremor-ataxia-central hypomyelination syndrome, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, odontoleukodystrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 10-77980162-C-T is Pathogenic according to our data. Variant chr10-77980162-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549570.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr10-77980162-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR3A	NM_007055.4 linkuse as main transcript	c.4003G>A	p.Gly1335Arg	missense_variant	30/31	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8 linkuse as main transcript	c.4003G>A	p.Gly1335Arg	missense_variant	30/31	1	NM_007055.4	ENSP00000361446	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251326

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neonatal pseudo-hydrocephalic progeroid syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	May 01, 2018	- -

Leukodystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2024

The p.Gly1335Arg variant in POLR3A has been reported in 1 individual with hypomyelinating leukodystrophy (PMID: 30323018), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs768222183). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 549570) and has been interpreted as likely pathogenic by Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital) and pathogenic by OMIM. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Gly1335Arg variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30323018). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1_supporting, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

-0.036

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-5.5

.;D

REVEL

Uncertain

0.64

Sift

Benign

0.066

.;T

Sift4G

Benign

0.074

T;T

Polyphen

1.0

.;D

Vest4

0.89

MutPred

0.58

.;Gain of catalytic residue at G1335 (P = 0.028);

MVP

0.93

MPC

0.54

ClinPred

0.93

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over