NM_004435.2:c.737C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004435.2(ENDOG):c.737C>T(p.Thr246Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,584,242 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 8 hom. )

Consequence

ENDOG
NM_004435.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017258972).

BP6

Variant 9-128822453-C-T is Benign according to our data. Variant chr9-128822453-C-T is described in ClinVar as Benign. ClinVar VariationId is 789305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

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>T	p.Thr246Ile	missense	Exon 3 of 3	NP_004426.2	Q14249
SPOUT1	NM_016390.4	MANE Select	c.*312G>A		3_prime_UTR	Exon 12 of 12	NP_057474.2
KYAT1-SPOUT1	NM_001414398.1		c.*312G>A		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>T	p.Thr246Ile	missense	Exon 3 of 3	ENSP00000361725.4	Q14249
SPOUT1	ENST00000361256.10	TSL:1 MANE Select	c.*312G>A		3_prime_UTR	Exon 12 of 12	ENSP00000354812.5	Q5T280
KYAT1	ENST00000651925.1		c.*2482G>A		3_prime_UTR	Exon 29 of 29	ENSP00000498386.1	A0A494C066

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

223

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00223

AC:

436

AN:

195746

AF XY:

0.00232

show subpopulations

Gnomad AFR exome

AF:

0.000166

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00942

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000334

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00271

GnomAD4 exome

AF:

0.00208

AC:

2973

AN:

1431884

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1484

AN XY:

709698

show subpopulations

African (AFR)

AF:

0.000397

AC:

AN:

32780

American (AMR)

AF:

0.00224

AC:

AN:

39664

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

213

AN:

25526

East Asian (EAS)

AF:

0.00

AC:

AN:

37998

South Asian (SAS)

AF:

0.00210

AC:

173

AN:

82476

European-Finnish (FIN)

AF:

0.000369

AC:

AN:

51476

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00209

AC:

2289

AN:

1096872

Other (OTH)

AF:

0.00268

AC:

159

AN:

59364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

211

422

634

845

1056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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

AF:

0.00146

AC:

223

AN:

152358

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41584

American (AMR)

AF:

0.00170

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000551

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00197

AC:

238

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

0.0024

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

M_CAP

Benign

0.021

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

7.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

REVEL

Benign

0.24

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.027

Polyphen

0.14

Vest4

0.30

MVP

0.40

MPC

0.33

ClinPred

0.036

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.77

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over