13-27637171-G-C

Variant names:

• chr13-27637171-G-C
• rs12584838
• ENST00000399697.7:c.27-11208G>C

Variant summary

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

The ENST00000399697.7(POLR1D):​c.27-11208G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 152,150 control chromosomes in the GnomAD database, including 855 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 0.091 (855 hom., cov: 32)
• Consequence: POLR1D ENST00000399697.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.429
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1D	NM_152705.3	c.27-11208G>C		intron_variant	Intron 1 of 2		NP_689918.1
POLR1D	NM_001206559.2	c.-58-11208G>C		intron_variant	Intron 1 of 2		NP_001193488.1
POLR1D	XM_047430381.1	c.27-11208G>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.27-11208G>C		intron_variant	Intron 1 of 2	1		ENSP00000382604.3
POLR1D	ENST00000621089.2	c.-58-11208G>C		intron_variant	Intron 1 of 2	1		ENSP00000478213.1
POLR1D	ENST00000489647.4	c.27-11208G>C		intron_variant	Intron 1 of 2	1		ENSP00000483656.1

Frequencies

GnomAD3 genomes AF: 0.0910 AC: 13838 AN: 152032 Hom.: 855 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0938

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.0909 AC: 13831 AN: 152150 Hom.: 855 Cov.: 32 AF XY: 0.0925 AC XY: 6883 AN XY: 74378

African (AFR) AF: 0.0449 AC: 1866 AN: 41518

American (AMR) AF: 0.116 AC: 1768 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1704 AN: 5166

South Asian (SAS) AF: 0.0751 AC: 362 AN: 4822

European-Finnish (FIN) AF: 0.0938 AC: 993 AN: 10588

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0954 AC: 6482 AN: 67980

Other (OTH) AF: 0.100 AC: 212 AN: 2116

Alfa AF: 0.0386 Hom.: 29

Bravo AF: 0.0924

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.61
PhyloP100		-0.43
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: rs12584838; hg19: chr13-28211308; COSMIC: COSV68800064;