13-27622003-T-G

Position:

• chr13-27622003-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_015972.4(POLR1D):​c.20T>G​(p.Leu7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLR1D NM_015972.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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]

POLR1D (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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=0.27045125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1D	NM_015972.4	c.20T>G	p.Leu7Arg	missense_variant	1/2	ENST00000302979.5	NP_057056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1D	ENST00000302979.5	c.20T>G	p.Leu7Arg	missense_variant	1/2	1	NM_015972.4	ENSP00000302478.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.20T>G (p.L7R) alteration is located in exon 1 (coding exon 1) of the POLR1D gene. This alteration results from a T to G substitution at nucleotide position 20, causing the leucine (L) at amino acid position 7 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	.;.;.;.;T;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.70	.;.;.;T;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.34	N;.;.;.;.;N;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.52	N;D;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.025	D;D;.;.;.;.;.
Sift4G	Uncertain	0.023	D;D;D;D;.;.;.
Vest4		0.48
MutPred		0.13		Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);Gain of MoRF binding (P = 0.0518);
MVP		0.95
MPC		0.33
ClinPred		0.54	D
GERP RS		3.6
Varity_R		0.25
gMVP		0.48

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: chr13-28196140;