rs35443467

chr2-86078184-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015425.6(POLR1A):c.1187G>A(p.Ser396Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,232 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (13 hom.)
• Consequence: POLR1A NM_015425.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, POLR1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.009562373).
• BP6: Variant 2-86078184-C-T is Benign according to our data. Variant chr2-86078184-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00717 (1091/152254) while in subpopulation AFR AF= 0.0243 (1008/41552). AF 95% confidence interval is 0.023. There are 14 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1086 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1A	NM_015425.6	c.1187G>A	p.Ser396Asn	missense_variant	10/34	ENST00000263857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1A	ENST00000263857.11	c.1187G>A	p.Ser396Asn	missense_variant	10/34	1	NM_015425.6	P2

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 1086 AN: 152136 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00206 AC: 511 AN: 248380 Hom.: 6 AF XY: 0.00154 AC XY: 208 AN XY: 134736

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000818 AC: 1195 AN: 1460978 Hom.: 13 Cov.: 33 AF XY: 0.000691 AC XY: 502 AN XY: 726768

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00717 AC: 1091 AN: 152254 Hom.: 14 Cov.: 33 AF XY: 0.00719 AC XY: 535 AN XY: 74432

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00130 Hom.: 4

Bravo AF: 0.00849

ESP6500AA AF: 0.0201 AC: 77

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.10
Sift	Benign	0.12	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.89	P;B
Vest4		0.61
MVP		0.55
MPC		1.2
ClinPred		0.0063	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs35443467; hg19: chr2-86305307;