19-617466-A-G

Position:

• chr19-617466-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005035.4(POLRMT):​c.3596T>C​(p.Leu1199Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,611,538 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (48 hom.)
• Consequence: POLRMT NM_005035.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.219

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049084723).
• BP6: Variant 19-617466-A-G is Benign according to our data. Variant chr19-617466-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 718243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLRMT	NM_005035.4	c.3596T>C	p.Leu1199Ser	missense_variant	20/21	ENST00000588649.7	NP_005026.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLRMT	ENST00000588649.7	c.3596T>C	p.Leu1199Ser	missense_variant	20/21	1	NM_005035.4	ENSP00000465759	P1
POLRMT	ENST00000590336.2	c.347T>C	p.Leu116Ser	missense_variant	6/6	3		ENSP00000468658
POLRMT	ENST00000587057.5	n.1086T>C		non_coding_transcript_exon_variant	3/4	5
POLRMT	ENST00000592633.5	n.322T>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 883 AN: 151932 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00331

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00852

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00616 AC: 1499 AN: 243530 Hom.: 5 AF XY: 0.00651 AC XY: 870 AN XY: 133620

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00661

Gnomad ASJ exome AF: 0.00549

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00354

Gnomad FIN exome AF: 0.00289

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00872

GnomAD4 exome AF: 0.00767 AC: 11191 AN: 1459488 Hom.: 48 Cov.: 38 AF XY: 0.00751 AC XY: 5455 AN XY: 726018

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00685

Gnomad4 ASJ exome AF: 0.00521

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.00319

Gnomad4 NFE exome AF: 0.00873

Gnomad4 OTH exome AF: 0.00795

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152050 Hom.: 10 Cov.: 33 AF XY: 0.00550 AC XY: 409 AN XY: 74314

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00975

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00331

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00761 Hom.: 2

Bravo AF: 0.00626

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00704 AC: 59

ExAC AF: 0.00587 AC: 708

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0105

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	POLRMT: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.7
DANN	Benign	0.32
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.45	T
Polyphen		0.0030	B
Vest4		0.15
MVP		0.16
MPC		0.029
ClinPred		0.00082	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.46

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: rs151287767; hg19: chr19-617466; COSMIC: COSV99241193; COSMIC: COSV99241193;