NM_007055.4:c.2830G>A

Variant names:

• chr10-77991125-C-T
• rs267608674
• NM_007055.4:c.2830G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_007055.4(POLR3A):​c.2830G>A​(p.Glu944Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: POLR3A NM_007055.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 4 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_007055.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41280073).

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.2830G>A	p.Glu944Lys	missense	Exon 21 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.2830G>A	p.Glu944Lys	missense	Exon 21 of 31	ENSP00000361446.3	O14802
	POLR3A	ENST00000865317.1		c.2830G>A	p.Glu944Lys	missense	Exon 21 of 30	ENSP00000535376.1
	POLR3A	ENST00000698731.1		c.2689G>A	p.Glu897Lys	missense	Exon 20 of 30	ENSP00000513898.1	A0A8V8TNX3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251158 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461530 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111712

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.098	T
Sift4G	Benign	0.13	T
Polyphen		0.37	B
Vest4		0.52
MutPred		0.59		Gain of ubiquitination at E944 (P = 0.0219)
MVP		0.78
MPC		0.40
ClinPred		0.45	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.72
Mutation Taster		=54/46	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: rs267608674; hg19: chr10-79750883;