chr13-27635186-A-G

Variant names:

• chr13-27635186-A-G
• rs535534
• ENST00000399697.7:c.26+13177A>G

Variant summary

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

The ENST00000399697.7(POLR1D):​c.26+13177A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,010 control chromosomes in the GnomAD database, including 21,034 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 0.49 (21034 hom., cov: 31)
• Consequence: POLR1D ENST00000399697.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 6 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399697.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1D	NM_152705.3		c.26+13177A>G		intron	N/A	NP_689918.1
	POLR1D	NM_001206559.2		c.-58-13193A>G		intron	N/A	NP_001193488.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1D	ENST00000399697.7	TSL:1	c.26+13177A>G		intron	N/A	ENSP00000382604.3
	POLR1D	ENST00000621089.2	TSL:1	c.-58-13193A>G		intron	N/A	ENSP00000478213.1
	POLR1D	ENST00000489647.4	TSL:1	c.26+13177A>G		intron	N/A	ENSP00000483656.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75097 AN: 151890 Hom.: 21020 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.494 AC: 75127 AN: 152010 Hom.: 21034 Cov.: 31 AF XY: 0.499 AC XY: 37080 AN XY: 74282

African (AFR) AF: 0.213 AC: 8822 AN: 41446

American (AMR) AF: 0.653 AC: 9975 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1906 AN: 3472

East Asian (EAS) AF: 0.823 AC: 4258 AN: 5174

South Asian (SAS) AF: 0.578 AC: 2788 AN: 4824

European-Finnish (FIN) AF: 0.587 AC: 6179 AN: 10524

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39254 AN: 67976

Other (OTH) AF: 0.534 AC: 1128 AN: 2112

Alfa AF: 0.557 Hom.: 14071

Bravo AF: 0.489

Asia WGS AF: 0.624 AC: 2171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.78
DANN	Benign	0.58
PhyloP100		-1.4
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: rs535534; hg19: chr13-28209323; COSMIC: COSV68800057;