NM_004435.2:c.733C>G

Variant names:

• chr9-128822449-C-G
• rs752642388
• NM_004435.2:c.733C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004435.2(ENDOG):​c.733C>G​(p.Arg245Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000189 in 1,587,588 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. R245L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38
• Publications: 0 publications found

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]

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

KYAT1 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

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.733C>G	p.Arg245Gly	missense	Exon 3 of 3	NP_004426.2	Q14249
	SPOUT1	NM_016390.4	MANE Select	c.*316G>C		3_prime_UTR	Exon 12 of 12	NP_057474.2
	KYAT1-SPOUT1	NM_001414398.1		c.*316G>C		3_prime_UTR	Exon 23 of 23	NP_001401327.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENDOG	ENST00000372642.5	TSL:1 MANE Select	c.733C>G	p.Arg245Gly	missense	Exon 3 of 3	ENSP00000361725.4	Q14249
	SPOUT1	ENST00000361256.10	TSL:1 MANE Select	c.*316G>C		3_prime_UTR	Exon 12 of 12	ENSP00000354812.5	Q5T280
	KYAT1	ENST00000651925.1		c.*2486G>C		3_prime_UTR	Exon 29 of 29	ENSP00000498386.1	A0A494C066

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000499 AC: 1 AN: 200356 AF XY: 0.00000926

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: 0.00000139 AC: 2 AN: 1435374 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 711778

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 40262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 38192

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098810

Other (OTH) AF: 0.00 AC: 0 AN: 59486

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.39	N
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.38
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.97	D
Vest4		0.79
MutPred		0.56		Loss of methylation at R245 (P = 0.0323)
MVP		0.73
MPC		1.1
ClinPred		0.84	D
GERP RS		4.7
Varity_R		0.31
gMVP		0.90
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs752642388; hg19: chr9-131584728;