13-27622931-A-C

Position:

• chr13-27622931-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_015972.4(POLR1D):​c.83A>C​(p.Glu28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLR1D NM_015972.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.590

Genes affected

POLR1D (HGNC:20422): (RNA polymerase I and III subunit D) The protein encoded by this gene is a component of the RNA polymerase I and RNA polymerase III complexes, which function in the synthesis of ribosomal RNA precursors and small RNAs, respectively. Mutations in this gene are a cause of Treacher Collins syndrome (TCS), a craniofacial development disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain DNA-directed RNA polymerases I and III subunit RPAC2 (size 132) in uniprot entity RPAC2_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_015972.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21325797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1D	NM_015972.4	c.83A>C	p.Glu28Ala	missense_variant	2/2	ENST00000302979.5	NP_057056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1D	ENST00000302979.5	c.83A>C	p.Glu28Ala	missense_variant	2/2	1	NM_015972.4	ENSP00000302478.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460784 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726814

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.027	.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	0.34	N;N;.
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.27	T;.;.
Sift4G	Benign	0.55	T;.;T
Vest4		0.16
MutPred		0.34		Gain of catalytic residue at A33 (P = 8e-04);Gain of catalytic residue at A33 (P = 8e-04);.;
MVP		0.95
MPC		0.24
ClinPred		0.24	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-28197068;