2-86082987-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015425.6(POLR1A):​c.817+95G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLR1A NM_015425.6 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 782890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 408886

African (AFR) AF: 0.00 AC: 0 AN: 19900

American (AMR) AF: 0.00 AC: 0 AN: 34220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35150

South Asian (SAS) AF: 0.00 AC: 0 AN: 66278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 516738

Other (OTH) AF: 0.00 AC: 0 AN: 37598

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.12
DANN	Benign	0.36
PhyloP100		-1.1

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;