13-27623299-C-T

Variant names:

• chr13-27623299-C-T
• rs7097
• NM_015972.4:c.*49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015972.4(POLR1D):​c.*49C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,609,720 control chromosomes in the GnomAD database, including 124,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9240 hom., cov: 32)
  • Exomes 𝑓: 0.39 (114871 hom.)
• Consequence: POLR1D NM_015972.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.428
• Publications: 57 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-27623299-C-T is Benign according to our data. Variant chr13-27623299-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1D	NM_015972.4	MANE Select	c.*49C>T		3_prime_UTR	Exon 2 of 2	NP_057056.1
	POLR1D	NM_001374407.1		c.*49C>T		3_prime_UTR	Exon 3 of 3	NP_001361336.1
	POLR1D	NM_152705.3		c.26+1290C>T		intron	N/A	NP_689918.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1D	ENST00000302979.5	TSL:1 MANE Select	c.*49C>T		3_prime_UTR	Exon 2 of 2	ENSP00000302478.4
	POLR1D	ENST00000399697.7	TSL:1	c.26+1290C>T		intron	N/A	ENSP00000382604.3
	POLR1D	ENST00000621089.2	TSL:1	c.-59+2159C>T		intron	N/A	ENSP00000478213.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48092 AN: 151934 Hom.: 9231 Cov.: 32

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.316

GnomAD2 exomes AF: 0.405 AC: 98061 AN: 241828 AF XY: 0.399

Gnomad AFR exome AF: 0.0959

Gnomad AMR exome AF: 0.577

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.471

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.391 AC: 570366 AN: 1457668 Hom.: 114871 Cov.: 33 AF XY: 0.391 AC XY: 283347 AN XY: 725138

African (AFR) AF: 0.0882 AC: 2950 AN: 33436

American (AMR) AF: 0.567 AC: 25207 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 9247 AN: 26106

East Asian (EAS) AF: 0.521 AC: 20667 AN: 39646

South Asian (SAS) AF: 0.382 AC: 32548 AN: 85276

European-Finnish (FIN) AF: 0.414 AC: 21739 AN: 52468

Middle Eastern (MID) AF: 0.331 AC: 1807 AN: 5466

European-Non Finnish (NFE) AF: 0.390 AC: 433436 AN: 1110532

Other (OTH) AF: 0.378 AC: 22765 AN: 60254

GnomAD4 genome AF: 0.316 AC: 48112 AN: 152052 Hom.: 9240 Cov.: 32 AF XY: 0.321 AC XY: 23828 AN XY: 74312

African (AFR) AF: 0.0977 AC: 4056 AN: 41516

American (AMR) AF: 0.449 AC: 6856 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1207 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2496 AN: 5168

South Asian (SAS) AF: 0.392 AC: 1890 AN: 4820

European-Finnish (FIN) AF: 0.400 AC: 4220 AN: 10542

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.385 AC: 26148 AN: 67954

Other (OTH) AF: 0.317 AC: 669 AN: 2110

Alfa AF: 0.364 Hom.: 36246

Bravo AF: 0.314

Asia WGS AF: 0.417 AC: 1448 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.14
DANN	Benign	0.69
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs7097; hg19: chr13-28197436; COSMIC: COSV57256159; COSMIC: COSV57256159;