rs503699

Variant names:

• chr13-27640597-G-C
• rs503699
• ENST00000399697.7:c.27-7782G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000399697.7(POLR1D):​c.27-7782G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,000 control chromosomes in the GnomAD database, including 7,791 homozygotes. 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: 𝑓 0.29 (7791 hom., cov: 32)
• Consequence: POLR1D ENST00000399697.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Treacher Collins syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Treacher-Collins syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1D	NM_152705.3	c.27-7782G>C		intron_variant	Intron 1 of 2		NP_689918.1
POLR1D	NM_001206559.2	c.-58-7782G>C		intron_variant	Intron 1 of 2		NP_001193488.1
POLR1D	XM_047430381.1	c.27-7782G>C		intron_variant	Intron 2 of 3		XP_047286337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1D	ENST00000399697.7	c.27-7782G>C		intron_variant	Intron 1 of 2	1		ENSP00000382604.3
POLR1D	ENST00000621089.2	c.-58-7782G>C		intron_variant	Intron 1 of 2	1		ENSP00000478213.1
POLR1D	ENST00000489647.4	c.27-7782G>C		intron_variant	Intron 1 of 2	1		ENSP00000483656.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43957 AN: 151882 Hom.: 7783 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.305

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.289 AC: 43979 AN: 152000 Hom.: 7791 Cov.: 32 AF XY: 0.292 AC XY: 21715 AN XY: 74262

African (AFR) AF: 0.0832 AC: 3451 AN: 41494

American (AMR) AF: 0.422 AC: 6435 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1077 AN: 3464

East Asian (EAS) AF: 0.224 AC: 1162 AN: 5182

South Asian (SAS) AF: 0.322 AC: 1555 AN: 4824

European-Finnish (FIN) AF: 0.429 AC: 4520 AN: 10536

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24609 AN: 67930

Other (OTH) AF: 0.305 AC: 645 AN: 2112

Alfa AF: 0.324 Hom.: 1156

Bravo AF: 0.281

Asia WGS AF: 0.296 AC: 1030 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.47
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs503699; hg19: chr13-28214734;