chr6-43519820-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_203290.4(POLR1C):​c.364T>A​(p.Phe122Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

POLR1C
NM_203290.4 missense

Scores

6
9
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 7.89
Variant links:
Genes affected
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.749
PP5
Variant 6-43519820-T-A is Pathogenic according to our data. Variant chr6-43519820-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548465.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLR1CNM_203290.4 linkuse as main transcriptc.364T>A p.Phe122Ile missense_variant 4/9 ENST00000642195.1 NP_976035.1
POLR1CNM_001318876.2 linkuse as main transcriptc.364T>A p.Phe122Ile missense_variant 4/11 NP_001305805.1
POLR1CNM_001363658.2 linkuse as main transcriptc.364T>A p.Phe122Ile missense_variant 4/10 NP_001350587.1
POLR1CXM_047419577.1 linkuse as main transcriptc.364T>A p.Phe122Ile missense_variant 4/9 XP_047275533.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLR1CENST00000642195.1 linkuse as main transcriptc.364T>A p.Phe122Ile missense_variant 4/9 NM_203290.4 ENSP00000496044 P1O15160-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingMyelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,-- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -
Treacher Collins syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D;.;D;.;D;.;.;.;.;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;.;D;D;.;D;T;T
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.4
.;.;M;.;M;.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.1
D;.;D;D;.;.;D;.;.;.
REVEL
Pathogenic
0.66
Sift
Benign
0.049
D;.;D;D;.;.;D;.;.;.
Sift4G
Benign
0.11
T;.;T;T;.;.;T;.;.;.
Polyphen
1.0
.;.;D;.;D;.;D;.;D;.
Vest4
0.78, 0.78, 0.80
MutPred
0.54
.;.;Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);Gain of loop (P = 0.0051);
MVP
0.90
MPC
0.49
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.81
gMVP
0.85

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

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

Other links and lift over

dbSNP: rs1554131502; hg19: chr6-43487558; API