2-86082987-C-T

Variant names:

• chr2-86082987-C-T
• rs2288118
• NM_015425.6:c.817+95G>A

Variant summary

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

The NM_015425.6(POLR1A):​c.817+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 933,548 control chromosomes in the GnomAD database, including 308,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42483 hom., cov: 31)
  • Exomes 𝑓: 0.82 (265599 hom.)
• Consequence: POLR1A NM_015425.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 9 publications found

Genes affected

POLR1A (HGNC:17264): (RNA polymerase I subunit A) The protein encoded by this gene is the largest subunit of the RNA polymerase I complex. The encoded protein represents the catalytic subunit of the complex, which transcribes DNA into ribosomal RNA precursors. Defects in this gene are a cause of the Cincinnati type of acrofacial dysostosis. [provided by RefSeq, May 2016]

POLR1A Gene-Disease associations (from GenCC):

• acrofacial dysostosis Cincinnati type

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• leukodystrophy, hypomyelinating, 27

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-86082987-C-T is Benign according to our data. Variant chr2-86082987-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1A	NM_015425.6	c.817+95G>A		intron_variant	Intron 7 of 33	ENST00000263857.11	NP_056240.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1A	ENST00000263857.11	c.817+95G>A		intron_variant	Intron 7 of 33	1	NM_015425.6	ENSP00000263857.6

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110672 AN: 151870 Hom.: 42475 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.848

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.781

GnomAD4 exome AF: 0.821 AC: 641291 AN: 781560 Hom.: 265599 AF XY: 0.823 AC XY: 335889 AN XY: 408210

African (AFR) AF: 0.459 AC: 9112 AN: 19860

American (AMR) AF: 0.843 AC: 28834 AN: 34188

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 17817 AN: 20078

East Asian (EAS) AF: 0.653 AC: 22935 AN: 35098

South Asian (SAS) AF: 0.820 AC: 54264 AN: 66202

European-Finnish (FIN) AF: 0.846 AC: 41224 AN: 48702

Middle Eastern (MID) AF: 0.816 AC: 3396 AN: 4160

European-Non Finnish (NFE) AF: 0.840 AC: 433323 AN: 515750

Other (OTH) AF: 0.810 AC: 30386 AN: 37522

GnomAD4 genome AF: 0.728 AC: 110723 AN: 151988 Hom.: 42483 Cov.: 31 AF XY: 0.731 AC XY: 54305 AN XY: 74282

African (AFR) AF: 0.465 AC: 19230 AN: 41366

American (AMR) AF: 0.794 AC: 12127 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3073 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3371 AN: 5176

South Asian (SAS) AF: 0.820 AC: 3964 AN: 4832

European-Finnish (FIN) AF: 0.848 AC: 8956 AN: 10560

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.845 AC: 57425 AN: 67996

Other (OTH) AF: 0.776 AC: 1638 AN: 2110

Alfa AF: 0.806 Hom.: 154992

Bravo AF: 0.716

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.21
PhyloP100		-1.1
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: rs2288118; hg19: chr2-86310110; COSMIC: COSV55697315; COSMIC: COSV55697315;