chr6-43517331-A-G

Variant names:

• chr6-43517331-A-G
• NM_203290.4:c.95A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_203290.4(POLR1C):​c.95A>G​(p.Asn32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N32I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLR1C NM_203290.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-43517331-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.37722474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1C	NM_203290.4	c.95A>G	p.Asn32Ser	missense_variant	Exon 2 of 9	ENST00000642195.1	NP_976035.1
POLR1C	NM_001318876.2	c.95A>G	p.Asn32Ser	missense_variant	Exon 2 of 9		NP_001305805.1
POLR1C	NM_001363658.2	c.95A>G	p.Asn32Ser	missense_variant	Exon 2 of 10		NP_001350587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1	c.95A>G	p.Asn32Ser	missense_variant	Exon 2 of 9		NM_203290.4	ENSP00000496044.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T;.;T;.;.;.;.;.
Eigen	Benign	0.038
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	.;.;D;D;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L;.;L;.;L;.;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.92	N;N;.;.;N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.30	T;T;.;.;T;.;.;.
Sift4G	Benign	0.40	T;T;.;.;T;.;.;.
Polyphen		0.15	B;.;B;.;B;.;B;.
Vest4		0.61
MutPred		0.31		Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);Gain of glycosylation at N32 (P = 0.0191);
MVP		0.76
MPC		0.070
ClinPred		0.85	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-43485069;