Genetic Variant NM_004435.2:c.329G>A (chr9-128819013-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_004435.2(ENDOG):c.329G>A(p.Arg110Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,332,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ENDOG
NM_004435.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

0 publications found

Variant links:

Genes affected

ENDOG (HGNC:3346): (endonuclease G) The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrion. The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA. [provided by RefSeq, Jul 2008]

ENDOG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a site Essential for catalytic activity (size 0) in uniprot entity NUCG_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004435.2. 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
	ENDOG	NM_004435.2	MANE Select	c.329G>A	p.Arg110Gln	missense	Exon 1 of 3	NP_004426.2	Q14249

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENDOG	ENST00000372642.5	TSL:1 MANE Select	c.329G>A	p.Arg110Gln	missense	Exon 1 of 3	ENSP00000361725.4	Q14249
	ENDOG	ENST00000854121.1		c.329G>A	p.Arg110Gln	missense	Exon 1 of 4	ENSP00000524180.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

79828

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1332826

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26772

American (AMR)

AF:

0.00

AC:

AN:

27916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22362

East Asian (EAS)

AF:

0.0000323

AC:

AN:

30938

South Asian (SAS)

AF:

0.0000137

AC:

AN:

72858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4422

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057686

Other (OTH)

AF:

0.00

AC:

AN:

55446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.16

MutPred

0.74

Loss of loop (P = 0.1242)

MVP

0.60

MPC

1.1

ClinPred

0.91

GERP RS

4.1

Varity_R

0.67

gMVP

0.74

Mutation Taster

=37/63

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over