rs41540414

Variant names:

• chr15-89330084-G-A
• rs41540414
• NM_002693.3:c.852C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89330084-G-A
• chr15-89330084-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002693.3(POLG):​c.852C>T​(p.Ile284Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,612,140 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.36
• Publications: 2 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]

POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-89330084-G-A is Benign according to our data. Variant chr15-89330084-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00309 (471/152306) while in subpopulation AFR AF = 0.0108 (448/41564). AF 95% confidence interval is 0.00995. There are 2 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.852C>T	p.Ile284Ile	synonymous	Exon 3 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.852C>T	p.Ile284Ile	synonymous	Exon 3 of 23	NP_001119603.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.*124C>T		downstream_gene	N/A	NP_001417049.1	A0A3B3IS91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.852C>T	p.Ile284Ile	synonymous	Exon 3 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.852C>T	p.Ile284Ile	synonymous	Exon 3 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.852C>T	p.Ile284Ile	synonymous	Exon 3 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 471 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000829 AC: 208 AN: 251006 AF XY: 0.000722

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000329 AC: 481 AN: 1459834 Hom.: 4 Cov.: 32 AF XY: 0.000275 AC XY: 200 AN XY: 726338

African (AFR) AF: 0.0112 AC: 373 AN: 33436

American (AMR) AF: 0.000537 AC: 24 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1110204

Other (OTH) AF: 0.000762 AC: 46 AN: 60328

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74478

African (AFR) AF: 0.0108 AC: 448 AN: 41564

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.1
DANN	Benign	0.74
PhyloP100		1.4

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: rs41540414; hg19: chr15-89873315;