dbSNP rs61737988: ENDOG:p.Arg245His (chr9-128822450-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004435.2(ENDOG):c.734G>A(p.Arg245His) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,433,104 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ENDOG
NM_004435.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

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 links:

ENSG00000286112 (HGNC:):

ENSG00000286112 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2 link	c.734G>A	p.Arg245His	missense_variant	Exon 3 of 3	ENST00000372642.5	NP_004426.2	Q14249E5KNL5
SPOUT1	NM_016390.4 link	c.*315C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000361256.10	NP_057474.2	Q5T280

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENDOG	ENST00000372642.5 link	c.734G>A	p.Arg245His	missense_variant	Exon 3 of 3	1	NM_004435.2	ENSP00000361725.4	Q14249
SPOUT1	ENST00000361256 link	c.*315C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5	Q5T280
ENSG00000286112	ENST00000651925 link	c.*2485C>T		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1	A0A494C066
SPOUT1	ENST00000467582 link	c.*275C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000473640.1	R4GNG4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000254

AC:

AN:

197028

Hom.:

AF XY:

0.0000283

AC XY:

AN XY:

106040

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 SAS exome

AF:

0.000155

Gnomad FIN exome

AF:

0.0000554

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1433104

Hom.:

Cov.:

AF XY:

0.00000844

AC XY:

AN XY:

710480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000525

Gnomad4 SAS exome

AF:

0.0000363

Gnomad4 FIN exome

AF:

0.0000388

Gnomad4 NFE exome

AF:

0.00000729

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.34

Sift

Uncertain

0.027

Sift4G

Uncertain

0.056

Polyphen

1.0

Vest4

0.27

MutPred

0.59

Loss of methylation at R245 (P = 0.0323);

MVP

0.82

MPC

1.1

ClinPred

0.64

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.088

gMVP

0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over