Variant 19-617472-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005035.4(POLRMT):c.3590A>G(p.Lys1197Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

POLRMT
NM_005035.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.645

Variant links:

Genes affected

POLRMT (HGNC:9200): (RNA polymerase mitochondrial) This gene encodes a mitochondrial DNA-directed RNA polymerase. The gene product is responsible for mitochondrial gene expression as well as for providing RNA primers for initiation of replication of the mitochondrial genome. Although this polypeptide has the same function as the three nuclear DNA-directed RNA polymerases, it is more closely related to RNA polymerases of phage and mitochondrial polymerases of lower eukaryotes. [provided by RefSeq, Jul 2008]

POLRMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.082461655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLRMT	NM_005035.4 linkuse as main transcript	c.3590A>G	p.Lys1197Arg	missense_variant	20/21	ENST00000588649.7	NP_005026.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
POLRMT	ENST00000588649.7 linkuse as main transcript	c.3590A>G	p.Lys1197Arg	missense_variant	20/21	1	NM_005035.4	ENSP00000465759	P1
POLRMT	ENST00000590336.2 linkuse as main transcript	c.341A>G	p.Lys114Arg	missense_variant	6/6	3		ENSP00000468658
POLRMT	ENST00000587057.5 linkuse as main transcript	n.1080A>G		non_coding_transcript_exon_variant	3/4	5
POLRMT	ENST00000592633.5 linkuse as main transcript	n.316A>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

243278

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459374

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725952

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.3590A>G (p.K1197R) alteration is located in exon 20 (coding exon 20) of the POLRMT gene. This alteration results from a A to G substitution at nucleotide position 3590, causing the lysine (K) at amino acid position 1197 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.5

DANN

Benign

0.73

DEOGEN2

Benign

0.0074

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.29

M_CAP

Benign

0.084

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

Sift4G

Benign

0.37

Polyphen

0.018

Vest4

0.18

MutPred

0.41

Loss of ubiquitination at K1197 (P = 0.0255);

MVP

0.37

MPC

0.023

ClinPred

0.058

GERP RS

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.081

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over