15-89321842-T-C

Variant names:

• chr15-89321842-T-C
• rs41549716
• NM_002693.3:c.2492A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002693.3(POLG):​c.2492A>G​(p.Tyr831Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00879 in 1,613,824 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y831Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (93 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 0.782
• Publications: 37 publications found

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014398247).
• BP6: Variant 15-89321842-T-C is Benign according to our data. Variant chr15-89321842-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00679 (1034/152272) while in subpopulation NFE AF = 0.011 (747/68006). AF 95% confidence interval is 0.0103. There are 12 homozygotes in GnomAd4. There are 491 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.2492A>G	p.Tyr831Cys	missense	Exon 16 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.2492A>G	p.Tyr831Cys	missense	Exon 16 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.2492A>G	p.Tyr831Cys	missense	Exon 16 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.2492A>G	p.Tyr831Cys	missense	Exon 16 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.2492A>G	p.Tyr831Cys	missense	Exon 16 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1034 AN: 152154 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00662 AC: 1664 AN: 251428 AF XY: 0.00649

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.00979

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00900 AC: 13155 AN: 1461552 Hom.: 93 Cov.: 32 AF XY: 0.00890 AC XY: 6469 AN XY: 727096

African (AFR) AF: 0.00140 AC: 47 AN: 33472

American (AMR) AF: 0.00186 AC: 83 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86254

European-Finnish (FIN) AF: 0.0174 AC: 929 AN: 53404

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11484 AN: 1111718

Other (OTH) AF: 0.00807 AC: 487 AN: 60382

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152272 Hom.: 12 Cov.: 33 AF XY: 0.00659 AC XY: 491 AN XY: 74460

African (AFR) AF: 0.00137 AC: 57 AN: 41554

American (AMR) AF: 0.00268 AC: 41 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 747 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00850 Hom.: 26

Bravo AF: 0.00507

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.00628 AC: 762

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	3	Progressive sclerosing poliodystrophy (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	POLG-related disorder (1)
-	-	1	POLG-Related Spectrum Disorders (1)
-	1	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.78
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.73
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.70
MVP		0.94
MPC		0.72
ClinPred		0.033	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.45
gMVP		0.85
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs41549716; hg19: chr15-89865073; COSMIC: COSV99175162; COSMIC: COSV99175162;