rs146253630

Variant names:

• chr10-77986123-T-C
• rs146253630
• NM_007055.4:c.2938A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-77986123-T-C
• chr10-77986123-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007055.4(POLR3A):​c.2938A>G​(p.Ile980Val) variant causes a missense change. The variant allele was found at a frequency of 0.00845 in 1,593,422 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (99 hom.)
• Consequence: POLR3A NM_007055.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.85
• Publications: 12 publications found

Genes affected

POLR3A (HGNC:30074): (RNA polymerase III subunit A) The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

POLR3A Gene-Disease associations (from GenCC):

• odontoleukodystrophy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• POLR3A-related disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Wiedemann-Rautenstrauch syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor-ataxia-central hypomyelination syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0091528).
• BP6: Variant 10-77986123-T-C is Benign according to our data. Variant chr10-77986123-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (875/152326) while in subpopulation NFE AF = 0.0093 (633/68036). AF 95% confidence interval is 0.0087. There are 4 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007055.4. 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
	POLR3A	NM_007055.4	MANE Select	c.2938A>G	p.Ile980Val	missense	Exon 22 of 31	NP_008986.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR3A	ENST00000372371.8	TSL:1 MANE Select	c.2938A>G	p.Ile980Val	missense	Exon 22 of 31	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.2938A>G	p.Ile980Val	missense	Exon 22 of 30	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.2797A>G	p.Ile933Val	missense	Exon 21 of 30	ENSP00000513898.1	A0A8V8TNX3

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00932

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00620 AC: 1558 AN: 251438 AF XY: 0.00600

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00874 AC: 12595 AN: 1441096 Hom.: 99 Cov.: 27 AF XY: 0.00843 AC XY: 6060 AN XY: 718598

African (AFR) AF: 0.00136 AC: 45 AN: 33066

American (AMR) AF: 0.00177 AC: 79 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 474 AN: 25988

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.00126 AC: 108 AN: 85842

European-Finnish (FIN) AF: 0.00230 AC: 123 AN: 53414

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5726

European-Non Finnish (NFE) AF: 0.0104 AC: 11327 AN: 1093068

Other (OTH) AF: 0.00727 AC: 434 AN: 59684

GnomAD4 genome AF: 0.00574 AC: 875 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74472

African (AFR) AF: 0.00212 AC: 88 AN: 41572

American (AMR) AF: 0.00190 AC: 29 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00930 AC: 633 AN: 68036

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00874 Hom.: 26

Bravo AF: 0.00578

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00636 AC: 772

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00853

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome (1)
-	-	1	Neonatal pseudo-hydrocephalic progeroid syndrome;C4706676:Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome (1)
-	-	1	not specified (1)
-	-	1	POLR3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.72	N
PhyloP100		5.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.098
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.44
MVP		0.56
MPC		0.29
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.094
gMVP		0.36
Mutation Taster		=96/4	polymorphism

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: rs146253630; hg19: chr10-79745881; COSMIC: COSV105297006; COSMIC: COSV105297006;