rs522071

Variant names:

• chr13-27637443-A-G
• rs522071
• ENST00000399697.7:c.27-10936A>G

Variant summary

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

The ENST00000399697.7(POLR1D):​c.27-10936A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,948 control chromosomes in the GnomAD database, including 7,819 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 (7819 hom., cov: 32)
• Consequence: POLR1D ENST00000399697.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• Publications: 4 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1D	NM_152705.3	c.27-10936A>G		intron_variant	Intron 1 of 2		NP_689918.1
POLR1D	NM_001206559.2	c.-58-10936A>G		intron_variant	Intron 1 of 2		NP_001193488.1
POLR1D	XM_047430381.1	c.27-10936A>G		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.27-10936A>G		intron_variant	Intron 1 of 2	1		ENSP00000382604.3
POLR1D	ENST00000621089.2	c.-58-10936A>G		intron_variant	Intron 1 of 2	1		ENSP00000478213.1
POLR1D	ENST00000489647.4	c.27-10936A>G		intron_variant	Intron 1 of 2	1		ENSP00000483656.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43707 AN: 151830 Hom.: 7814 Cov.: 32

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.288 AC: 43724 AN: 151948 Hom.: 7819 Cov.: 32 AF XY: 0.291 AC XY: 21633 AN XY: 74254

African (AFR) AF: 0.0737 AC: 3053 AN: 41446

American (AMR) AF: 0.422 AC: 6446 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1078 AN: 3468

East Asian (EAS) AF: 0.238 AC: 1230 AN: 5158

South Asian (SAS) AF: 0.323 AC: 1556 AN: 4810

European-Finnish (FIN) AF: 0.428 AC: 4510 AN: 10528

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24651 AN: 67958

Other (OTH) AF: 0.303 AC: 641 AN: 2114

Alfa AF: 0.348 Hom.: 10985

Bravo AF: 0.279

Asia WGS AF: 0.300 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		0.036
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: rs522071; hg19: chr13-28211580;