dbSNP rs796052172: POLRMT:p.Glu900Lys (chr19-620430-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_005035.4(POLRMT):c.2698G>A(p.Glu900Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLRMT
NM_005035.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.44

Publications

1 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

BP6

Variant 19-620430-C-T is Benign according to our data. Variant chr19-620430-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 207890.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLRMT	NM_005035.4 link	c.2698G>A	p.Glu900Lys	missense_variant	Exon 11 of 21	ENST00000588649.7	NP_005026.3	O00411Q4G0F4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLRMT	ENST00000588649.7 link	c.2698G>A	p.Glu900Lys	missense_variant	Exon 11 of 21	1	NM_005035.4	ENSP00000465759.2		O00411

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1446148

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.00

AC:

AN:

43308

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25754

East Asian (EAS)

AF:

0.0000513

AC:

AN:

38982

South Asian (SAS)

AF:

0.00

AC:

AN:

83792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105178

Other (OTH)

AF:

0.00

AC:

AN:

59710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Medical Research Institute, Tokyo Medical and Dental University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

4.0

PhyloP100

7.4

PrimateAI

Uncertain

0.63

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.85

MutPred

0.83

Gain of ubiquitination at E900 (P = 0.0539);

MVP

0.64

MPC

0.84

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.98

gMVP

0.91

Mutation Taster

=20/80

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over