rs141471029

Variant names:

• chr6-43519384-A-G
• rs141471029
• NM_203290.4:c.193A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_203290.4(POLR1C):​c.193A>G​(p.Met65Val) variant causes a missense change. The variant allele was found at a frequency of 0.00146 in 1,614,026 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: POLR1C NM_203290.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 O:1
• Conservation: PhyloP100: 6.98
• Publications: 12 publications found

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

ENSG00000271754 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06145224).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000939 (143/152308) while in subpopulation NFE AF = 0.00171 (116/68020). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1C	NM_203290.4	MANE Select	c.193A>G	p.Met65Val	missense	Exon 3 of 9	NP_976035.1
	POLR1C	NM_001318876.2		c.193A>G	p.Met65Val	missense	Exon 3 of 9	NP_001305805.1
	POLR1C	NM_001363658.2		c.193A>G	p.Met65Val	missense	Exon 3 of 10	NP_001350587.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1C	ENST00000642195.1	MANE Select	c.193A>G	p.Met65Val	missense	Exon 3 of 9	ENSP00000496044.1
	POLR1C	ENST00000304004.7	TSL:1	c.193A>G	p.Met65Val	missense	Exon 3 of 9	ENSP00000307212.3
	POLR1C	ENST00000646433.1		c.193A>G	p.Met65Val	missense	Exon 3 of 9	ENSP00000494368.1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000851 AC: 214 AN: 251490 AF XY: 0.000853

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00151 AC: 2212 AN: 1461718 Hom.: 4 Cov.: 30 AF XY: 0.00147 AC XY: 1069 AN XY: 727182

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00185 AC: 2059 AN: 1111860

Other (OTH) AF: 0.00128 AC: 77 AN: 60388

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74472

African (AFR) AF: 0.000265 AC: 11 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.000839

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.00202

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Hypomyelinating leukodystrophy 11 (4)
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	-	Hearing impairment (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	POLR1C-related disorder (1)
-	1	-	Treacher Collins syndrome 3;C4225305:Hypomyelinating leukodystrophy 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.58
Sift	Benign	0.030	D
Sift4G	Benign	0.095	T
Polyphen		0.067	B
Vest4		0.93
MVP		0.78
MPC		0.13
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.77
gMVP		0.77
Mutation Taster		=30/70	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs141471029; hg19: chr6-43487122;