9-37777622-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_144964.4(TRMT10B):c.866A>T(p.Tyr289Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,658 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign 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 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.19

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 -12 ACMG points.

• BP6: Variant 9-37777622-A-T is Benign according to our data. Variant chr9-37777622-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 801361.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.866A>T	p.Tyr289Phe	missense_variant	9/9	ENST00000297994.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT10B	ENST00000297994.4	c.866A>T	p.Tyr289Phe	missense_variant	9/9	1	NM_144964.4	P1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 320 AN: 151896 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00210 AC: 523 AN: 249530 Hom.: 3 AF XY: 0.00220 AC XY: 298 AN XY: 135382

Gnomad AFR exome AF: 0.000388

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: 0.00890

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00240 AC: 3501 AN: 1461644 Hom.: 11 Cov.: 30 AF XY: 0.00239 AC XY: 1738 AN XY: 727136

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: 0.00799

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00211 AC: 320 AN: 152014 Hom.: 1 Cov.: 30 AF XY: 0.00248 AC XY: 184 AN XY: 74302

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00976

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000934 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	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EXOSC3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Benign	0.69
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.059
Sift	Benign	0.55	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.010	B;B
Vest4		0.22
MVP		0.099
MPC		0.048
ClinPred		0.039	T
GERP RS		5.5
Varity_R		0.30
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199618338; hg19: chr9-37777619; COSMIC: COSV53050445; COSMIC: COSV53050445;