chr10-77975616-C-T

Variant names:

• chr10-77975616-C-T
• rs12572507
• NM_007055.4:c.*1862G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007055.4(POLR3A):​c.*1862G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 152,454 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (294 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1 hom.)
• Consequence: POLR3A NM_007055.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.732
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-77975616-C-T is Benign according to our data. Variant chr10-77975616-C-T is described in ClinVar as Benign. ClinVar VariationId is 300994.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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.*1862G>A		3_prime_UTR	Exon 31 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.*1862G>A		3_prime_UTR	Exon 31 of 31	ENSP00000361446.3	O14802
	POLR3A	ENST00000912220.1		c.*1862G>A		splice_region	Exon 30 of 30	ENSP00000582279.1
	POLR3A	ENST00000865317.1		c.*1862G>A		3_prime_UTR	Exon 30 of 30	ENSP00000535376.1

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6170 AN: 152232 Hom.: 295 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0838

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0385 AC: 4 AN: 104 Hom.: 1 Cov.: 0 AF XY: 0.0147 AC XY: 1 AN XY: 68

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0385 AC: 1 AN: 26

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64

Other (OTH) AF: 0.375 AC: 3 AN: 8

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0405 AC: 6177 AN: 152350 Hom.: 294 Cov.: 32 AF XY: 0.0454 AC XY: 3380 AN XY: 74512

African (AFR) AF: 0.0201 AC: 837 AN: 41590

American (AMR) AF: 0.0842 AC: 1288 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.225 AC: 1169 AN: 5190

South Asian (SAS) AF: 0.145 AC: 701 AN: 4830

European-Finnish (FIN) AF: 0.0309 AC: 328 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1673 AN: 68034

Other (OTH) AF: 0.0478 AC: 101 AN: 2112

Alfa AF: 0.0332 Hom.: 305

Bravo AF: 0.0414

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Leukoencephalopathy, ataxia, hypodontia, hypomyelination syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.85
PhyloP100		0.73
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: rs12572507; hg19: chr10-79735374;