9-128822453-C-T

Position:

• chr9-128822453-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.31

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]

KYAT1-SPOUT1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 789305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENDOG	NM_004435.2	c.737C>T	p.Thr246Ile	missense_variant	3/3	ENST00000372642.5
SPOUT1	NM_016390.4	c.*312G>A		3_prime_UTR_variant	12/12	ENST00000361256.10
KYAT1-SPOUT1	NR_182311.1	n.3354G>A		non_coding_transcript_exon_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENDOG	ENST00000372642.5	c.737C>T	p.Thr246Ile	missense_variant	3/3	1	NM_004435.2	P1
SPOUT1	ENST00000361256.10	c.*312G>A		3_prime_UTR_variant	12/12	1	NM_016390.4	P1
SPOUT1	ENST00000467582.1	c.*272G>A		3_prime_UTR_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152240 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00223 AC: 436 AN: 195746 Hom.: 3 AF XY: 0.00232 AC XY: 244 AN XY: 105286

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 SAS exome AF: 0.00252

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.: 8 Cov.: 31 AF XY: 0.00209 AC XY: 1484 AN XY: 709698

Gnomad4 AFR exome AF: 0.000397

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.000369

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74502

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000640 Hom.: 0

Bravo AF: 0.00160

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00197 AC: 238

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.0024
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.027	D
Polyphen		0.14	B
Vest4		0.30
MVP		0.40
MPC		0.33
ClinPred		0.036	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs61737987; hg19: chr9-131584732;