dbSNP rs41553913: POLRMT:p.Phe400Leu (chr19-623546-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005035.4(POLRMT):c.1198T>C(p.Phe400Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0161 in 1,613,624 control chromosomes in the GnomAD database, including 925 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 0.046 ( 433 hom., cov: 33)

Exomes 𝑓: 0.013 ( 492 hom. )

Consequence

POLRMT
NM_005035.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.43

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020318627).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLRMT	NM_005035.4 link	c.1198T>C	p.Phe400Leu	missense_variant	Exon 6 of 21	ENST00000588649.7	NP_005026.3	O00411Q4G0F4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLRMT	ENST00000588649.7 link	c.1198T>C	p.Phe400Leu	missense_variant	Exon 6 of 21	1	NM_005035.4	ENSP00000465759.2	O00411
POLRMT	ENST00000590573.4 link	c.964T>C	p.Phe322Leu	missense_variant	Exon 4 of 4	3		ENSP00000466504.4	K7EMH3
POLRMT	ENST00000590709.3 link	n.631T>C		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0463

AC:

7039

AN:

152142

Hom.:

431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00922

Gnomad OTH

AF:

0.0468

GnomAD3 exomes

AF:

0.0183

AC:

4586

AN:

250640

Hom.:

201

AF XY:

0.0156

AC XY:

2117

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0321

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00761

Gnomad FIN exome

AF:

0.00328

Gnomad NFE exome

AF:

0.00990

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0130

AC:

18980

AN:

1461364

Hom.:

492

Cov.:

AF XY:

0.0124

AC XY:

8995

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.147

Gnomad4 AMR exome

AF:

0.0130

Gnomad4 ASJ exome

AF:

0.0322

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00815

Gnomad4 FIN exome

AF:

0.00362

Gnomad4 NFE exome

AF:

0.00918

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0463

AC:

7053

AN:

152260

Hom.:

433

Cov.:

AF XY:

0.0442

AC XY:

3288

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.139

Gnomad4 AMR

AF:

0.0216

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00922

Gnomad4 OTH

AF:

0.0464

Alfa

AF:

0.0259

Hom.:

Bravo

AF:

0.0530

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.137

AC:

604

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.0206

AC:

2496

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.56

Sift4G

Benign

0.31

T;.

Polyphen

0.18

B;.

Vest4

0.23

MutPred

0.68

Gain of disorder (P = 0.0618);.;

MPC

0.65

ClinPred

0.032

GERP RS

4.6

Varity_R

0.74

gMVP

0.67

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over