rs2307438

Variant names:

• chr15-89317555-A-C
• rs2307438
• NM_002693.3:c.3483-19T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89317555-A-C
• chr15-89317555-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.3483-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,608,966 control chromosomes in the GnomAD database, including 132,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14769 hom., cov: 31)
  • Exomes 𝑓: 0.40 (117806 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.383
• Publications: 20 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]

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FANCI Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-89317555-A-C is Benign according to our data. Variant chr15-89317555-A-C is described in ClinVar as Benign. ClinVar VariationId is 138763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

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.3483-19T>G		intron	N/A	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3483-19T>G		intron	N/A	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.3483-19T>G		intron	N/A	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3483-19T>G		intron	N/A	ENSP00000399851.2	P54098
	FANCI	ENST00000940788.1		c.*1096A>C		3_prime_UTR	Exon 38 of 38	ENSP00000610847.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66310 AN: 151604 Hom.: 14747 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.421 AC: 105528 AN: 250716 AF XY: 0.417

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.399 AC: 581755 AN: 1457244 Hom.: 117806 Cov.: 33 AF XY: 0.399 AC XY: 289157 AN XY: 725206

African (AFR) AF: 0.520 AC: 17373 AN: 33378

American (AMR) AF: 0.488 AC: 21800 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10301 AN: 26098

East Asian (EAS) AF: 0.339 AC: 13451 AN: 39684

South Asian (SAS) AF: 0.398 AC: 34272 AN: 86176

European-Finnish (FIN) AF: 0.471 AC: 24943 AN: 53006

Middle Eastern (MID) AF: 0.376 AC: 2168 AN: 5764

European-Non Finnish (NFE) AF: 0.391 AC: 432905 AN: 1108158

Other (OTH) AF: 0.407 AC: 24542 AN: 60266

GnomAD4 genome AF: 0.437 AC: 66376 AN: 151722 Hom.: 14769 Cov.: 31 AF XY: 0.443 AC XY: 32825 AN XY: 74138

African (AFR) AF: 0.518 AC: 21440 AN: 41352

American (AMR) AF: 0.421 AC: 6425 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3466

East Asian (EAS) AF: 0.354 AC: 1820 AN: 5136

South Asian (SAS) AF: 0.392 AC: 1879 AN: 4796

European-Finnish (FIN) AF: 0.485 AC: 5108 AN: 10528

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27064 AN: 67886

Other (OTH) AF: 0.409 AC: 864 AN: 2110

Alfa AF: 0.425 Hom.: 5323

Bravo AF: 0.440

Asia WGS AF: 0.376 AC: 1306 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Progressive sclerosing poliodystrophy (3)
-	-	2	not provided (2)
-	-	1	Mitochondrial DNA depletion syndrome 4b (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (1)
-	-	1	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2307438; hg19: chr15-89860786; COSMIC: COSV51521392; COSMIC: COSV51521392;