9-37777623-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_144964.4(TRMT10B):c.867C>A(p.Tyr289Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,866 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: TRMT10B NM_144964.4 stop_gained
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43

Genes affected

TRMT10B (HGNC:26454): (tRNA methyltransferase 10B) Enables tRNA (guanine-N1-)-methyltransferase activity. Predicted to be involved in mitochondrial tRNA processing. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM4: Stoplost variant in NM_144964.4 Downstream stopcodon found after 341 codons.
• BP6: Variant 9-37777623-C-A is Benign according to our data. Variant chr9-37777623-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 801362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT10B	NM_144964.4	c.867C>A	p.Tyr289Ter	stop_gained	9/9	ENST00000297994.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10B	ENST00000297994.4	c.867C>A	p.Tyr289Ter	stop_gained	9/9	1	NM_144964.4	P1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152072 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00973

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00210 AC: 523 AN: 249550 Hom.: 3 AF XY: 0.00220 AC XY: 298 AN XY: 135396

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00891

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00240 AC: 3502 AN: 1461674 Hom.: 11 Cov.: 30 AF XY: 0.00239 AC XY: 1738 AN XY: 727154

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.00800

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152192 Hom.: 1 Cov.: 30 AF XY: 0.00247 AC XY: 184 AN XY: 74402

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00973

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00135

ExAC AF: 0.00197 AC: 238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00231

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EXOSC3: BS2; TRMT10B: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.18
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200754365; hg19: chr9-37777620; COSMIC: COSV53050455; COSMIC: COSV53050455;