Genetic Variant NM_203290.4:c.95A>T (chr6-43517331-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_203290.4(POLR1C):c.95A>T(p.Asn32Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

POLR1C
NM_203290.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 6.38

Publications

13 publications found

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]

POLR1C Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Treacher Collins syndrome 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Treacher-Collins syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_203290.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-43517331-A-T is Pathogenic according to our data. Variant chr6-43517331-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 204588.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203290.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLR1C	NM_203290.4	MANE Select	c.95A>T	p.Asn32Ile	missense	Exon 2 of 9	NP_976035.1
POLR1C	NM_001318876.2		c.95A>T	p.Asn32Ile	missense	Exon 2 of 9	NP_001305805.1
POLR1C	NM_001363658.2		c.95A>T	p.Asn32Ile	missense	Exon 2 of 10	NP_001350587.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLR1C	ENST00000642195.1	MANE Select	c.95A>T	p.Asn32Ile	missense	Exon 2 of 9	ENSP00000496044.1
POLR1C	ENST00000304004.7	TSL:1	c.95A>T	p.Asn32Ile	missense	Exon 2 of 9	ENSP00000307212.3
POLR1C	ENST00000945270.1		c.95A>T	p.Asn32Ile	missense	Exon 2 of 9	ENSP00000615329.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypomyelinating leukodystrophy 11 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.7

PhyloP100

6.4

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.67

Sift

Benign

0.16

Sift4G

Benign

0.27

Polyphen

0.89

Vest4

0.95

MutPred

0.47

Gain of sheet (P = 0.0221)

MVP

0.84

MPC

0.16

ClinPred

0.98

GERP RS

5.3

PromoterAI

0.048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.86

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over