Genetic Variant NM_015425.6:c.817+95G>A (chr2-86082987-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.09

Publications

9 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
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

POLR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015425.6. 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
	POLR1A	NM_015425.6	MANE Select	c.817+95G>A		intron	N/A	NP_056240.2	O95602

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLR1A	ENST00000263857.11	TSL:1 MANE Select	c.817+95G>A	intron	N/A	ENSP00000263857.6	O95602
POLR1A	ENST00000409681.1	TSL:5	c.817+95G>A	intron	N/A	ENSP00000386300.1	B9ZVN9
POLR1A	ENST00000931492.1		c.817+95G>A	intron	N/A	ENSP00000601551.1

Frequencies

GnomAD3 genomes

AF:

0.729

AC:

110672

AN:

151870

Hom.:

42475

Cov.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

5240

10480

15721

20961

26201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6232

12464

18696

24928

31160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.728

AC:

110723

AN:

151988

Hom.:

42483

Cov.:

AF XY:

0.731

AC XY:

54305

AN XY:

74282

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1329

2658

3988

5317

6646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.806

Hom.:

154992

Bravo

AF:

0.716

Asia WGS

AF:

0.716

AC:

2490

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.14

(source)

DANN

Benign

0.21

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over