9-128822807-G-C

Variant names:

• chr9-128822807-G-C
• rs35677895
• NM_016390.4:c.1089C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016390.4(SPOUT1):​c.1089C>G​(p.Ala363Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,591,632 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (18 hom., cov: 34)
  • Exomes 𝑓: 0.018 (295 hom.)
• Consequence: SPOUT1 NM_016390.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.288

Genes affected

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]

ENSG00000286112 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038615167).
• BP6: Variant 9-128822807-G-C is Benign according to our data. Variant chr9-128822807-G-C is described in ClinVar as [Benign]. Clinvar id is 3041881.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.288 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2086/152364) while in subpopulation NFE AF= 0.0207 (1408/68032). AF 95% confidence interval is 0.0198. There are 18 homozygotes in gnomad4. There are 971 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOUT1	NM_016390.4	c.1089C>G	p.Ala363Ala	synonymous_variant	Exon 12 of 12	ENST00000361256.10	NP_057474.2
ENDOG	NM_004435.2	c.*197G>C		downstream_gene_variant		ENST00000372642.5	NP_004426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOUT1	ENST00000361256.10	c.1089C>G	p.Ala363Ala	synonymous_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5
ENSG00000286112	ENST00000651925	c.*2128C>G		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1
ENDOG	ENST00000372642.5	c.*197G>C		downstream_gene_variant		1	NM_004435.2	ENSP00000361725.4

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2085 AN: 152246 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0135 AC: 2877 AN: 213716 Hom.: 31 AF XY: 0.0131 AC XY: 1510 AN XY: 115088

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00913

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00273

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0183 AC: 26324 AN: 1439268 Hom.: 295 Cov.: 35 AF XY: 0.0179 AC XY: 12753 AN XY: 713844

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00990

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0209

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0137 AC: 2086 AN: 152364 Hom.: 18 Cov.: 34 AF XY: 0.0130 AC XY: 971 AN XY: 74510

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0185 Hom.: 10

Bravo AF: 0.0129

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00297 AC: 13

ESP6500EA AF: 0.0183 AC: 157

ExAC AF: 0.0116 AC: 1400

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SPOUT1-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.4
DANN	Benign	0.83
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
Sift4G	Uncertain	0.0040	D
ClinPred		0.0027	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35677895; hg19: chr9-131585086;