Genetic Variant NM_005035.4:c.1198T>C (chr19-623546-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation deficiency 55
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

POLRMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.0183

AC:

4586

AN:

250640

AF XY:

0.0156

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 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

African (AFR)

AF:

0.147

AC:

4905

AN:

33474

American (AMR)

AF:

0.0130

AC:

580

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0322

AC:

842

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00815

AC:

703

AN:

86254

European-Finnish (FIN)

AF:

0.00362

AC:

192

AN:

53006

Middle Eastern (MID)

AF:

0.0427

AC:

245

AN:

5740

European-Non Finnish (NFE)

AF:

0.00918

AC:

10207

AN:

1111966

Other (OTH)

AF:

0.0216

AC:

1304

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1088

2176

3263

4351

5439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

488

976

1464

1952

2440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0463

AC:

7053

AN:

152260

Hom.:

433

Cov.:

AF XY:

0.0442

AC XY:

3288

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.139

AC:

5796

AN:

41550

American (AMR)

AF:

0.0216

AC:

331

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00664

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00922

AC:

627

AN:

68010

Other (OTH)

AF:

0.0464

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

315

630

945

1260

1575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0157

Hom.:

130

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

(source)

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;.

PhyloP100

4.4

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

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over