rs41553913

Positions:

• chr19-623546-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43

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]

ACMG classification

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/exons	MANE	UniProt
POLRMT	NM_005035.4	c.1198T>C	p.Phe400Leu	missense_variant	6/21	ENST00000588649.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLRMT	ENST00000588649.7	c.1198T>C	p.Phe400Leu	missense_variant	6/21	1	NM_005035.4	P1
POLRMT	ENST00000590573.4	c.964T>C	p.Phe322Leu	missense_variant	4/4	3
POLRMT	ENST00000590709.3	n.631T>C		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7039 AN: 152142 Hom.: 431 Cov.: 33

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

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.: 34 AF XY: 0.0124 AC XY: 8995 AN XY: 727026

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.: 33 AF XY: 0.0442 AC XY: 3288 AN XY: 74450

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.: 91

Bravo AF: 0.0530

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.137 AC: 604

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.0206 AC: 2496

Asia WGS AF: 0.0100 AC: 35 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	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.000016	P;P
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs41553913; hg19: chr19-623546; COSMIC: COSV73933075; COSMIC: COSV73933075;