Genetic Variant ENDOG:p.Thr246Asn (chr9-128822453-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004435.2(ENDOG):c.737C>A(p.Thr246Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T246I) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ENDOG
NM_004435.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.31

Publications

2 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:

SPOUT1 (HGNC:26933): (SPOUT domain containing methyltransferase 1) Enables miRNA binding activity. Involved in maintenance of centrosome location and production of miRNAs involved in gene silencing by miRNA. Located in kinetochore; mitotic spindle; and spindle pole centrosome. [provided by Alliance of Genome Resources, Apr 2022]

SPOUT1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SPOUT1 links:

KYAT1 (HGNC:):

KYAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENDOG	NM_004435.2	MANE Select	c.737C>A	p.Thr246Asn	missense	Exon 3 of 3	NP_004426.2	Q14249
SPOUT1	NM_016390.4	MANE Select	c.*312G>T		3_prime_UTR	Exon 12 of 12	NP_057474.2
KYAT1-SPOUT1	NM_001414398.1		c.*312G>T		3_prime_UTR	Exon 23 of 23	NP_001401327.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENDOG	ENST00000372642.5	TSL:1 MANE Select	c.737C>A	p.Thr246Asn	missense	Exon 3 of 3	ENSP00000361725.4	Q14249
SPOUT1	ENST00000361256.10	TSL:1 MANE Select	c.*312G>T		3_prime_UTR	Exon 12 of 12	ENSP00000354812.5	Q5T280
KYAT1	ENST00000651925.1		c.*2482G>T		3_prime_UTR	Exon 29 of 29	ENSP00000498386.1	A0A494C066

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1431884

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32780

American (AMR)

AF:

0.00

AC:

AN:

39664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25526

East Asian (EAS)

AF:

0.00

AC:

AN:

37998

South Asian (SAS)

AF:

0.00

AC:

AN:

82476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1096872

Other (OTH)

AF:

0.00

AC:

AN:

59364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

0.070

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

7.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.93

REVEL

Benign

0.20

Sift

Uncertain

0.012

Sift4G

Uncertain

0.017

Polyphen

0.24

Vest4

0.38

MutPred

0.63

Loss of glycosylation at T246 (P = 0.1014)

MVP

0.38

MPC

0.34

ClinPred

0.73

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.79

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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