NM_203290.4:c.364T>A

Variant names:

• chr6-43519820-T-A
• rs1554131502
• NM_203290.4:c.364T>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.89

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]

ENSG00000271754 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
POLR1C	NM_203290.4	c.364T>A	p.Phe122Ile	missense_variant	Exon 4 of 9	ENST00000642195.1	NP_976035.1
POLR1C	NM_001318876.2	c.364T>A	p.Phe122Ile	missense_variant	Exon 4 of 9		NP_001305805.1
POLR1C	NM_001363658.2	c.364T>A	p.Phe122Ile	missense_variant	Exon 4 of 10		NP_001350587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1	c.364T>A	p.Phe122Ile	missense_variant	Exon 4 of 9		NM_203290.4	ENSP00000496044.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:1 Uncertain:1

-

Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Treacher Collins syndrome 3 Pathogenic:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
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

Other links and lift over

dbSNP: rs1554131502; hg19: chr6-43487558;