10-77975513-T-C

Variant names:

• chr10-77975513-T-C
• rs2241546
• NM_007055.4:c.*1965A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007055.4(POLR3A):​c.*1965A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,190 control chromosomes in the GnomAD database, including 5,130 homozygotes. 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: 𝑓 0.25 (5129 hom., cov: 32)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: POLR3A NM_007055.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 0 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: Illumina, Orphanet
• Wiedemann-Rautenstrauch syndrome

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR3A	NM_007055.4	c.*1965A>G		3_prime_UTR_variant	Exon 31 of 31	ENST00000372371.8	NP_008986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR3A	ENST00000372371.8	c.*1965A>G		3_prime_UTR_variant	Exon 31 of 31	1	NM_007055.4	ENSP00000361446.3

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37450 AN: 151998 Hom.: 5112 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.216 AC: 16 AN: 74 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 10 AN XY: 40

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 6 AN: 24

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.184 AC: 7 AN: 38

Other (OTH) AF: 0.250 AC: 2 AN: 8

GnomAD4 genome AF: 0.247 AC: 37513 AN: 152116 Hom.: 5129 Cov.: 32 AF XY: 0.248 AC XY: 18433 AN XY: 74366

African (AFR) AF: 0.302 AC: 12524 AN: 41484

American (AMR) AF: 0.254 AC: 3876 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 771 AN: 3472

East Asian (EAS) AF: 0.515 AC: 2661 AN: 5164

South Asian (SAS) AF: 0.295 AC: 1422 AN: 4814

European-Finnish (FIN) AF: 0.177 AC: 1877 AN: 10586

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.198 AC: 13441 AN: 67996

Other (OTH) AF: 0.247 AC: 521 AN: 2110

Alfa AF: 0.204 Hom.: 1646

Bravo AF: 0.255

Asia WGS AF: 0.428 AC: 1487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.39
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2241546; hg19: chr10-79735271;