chr2-28850337-C-G

Position:

• chr2-28850337-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000306108.10(TRMT61B):​c.1381G>C​(p.Gly461Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRMT61B ENST00000306108.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.578

Genes affected

TRMT61B (HGNC:26070): (tRNA methyltransferase 61B) Enables mRNA (adenine-N1-)-methyltransferase activity; rRNA (adenine) methyltransferase activity; and tRNA (adenine-N1-)-methyltransferase activity. Involved in mRNA methylation; mitochondrial tRNA methylation; and protein homooligomerization. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SPDYA (HGNC:30613): (speedy/RINGO cell cycle regulator family member A) Enables protein kinase activator activity and protein kinase binding activity. Involved in several processes, including G1/S transition of mitotic cell cycle; positive regulation of cell population proliferation; and positive regulation of protein kinase activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TRMT61B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT61B	NM_017910.4	c.1381G>C	p.Gly461Arg	missense_variant	6/7	ENST00000306108.10	NP_060380.3
SPDYA	NM_182756.4	c.*396C>G		3_prime_UTR_variant	8/8	ENST00000334056.10	NP_877433.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT61B	ENST00000306108.10	c.1381G>C	p.Gly461Arg	missense_variant	6/7	1	NM_017910.4	ENSP00000302801.5
SPDYA	ENST00000334056.10	c.*396C>G		3_prime_UTR_variant	8/8	1	NM_182756.4	ENSP00000335628.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457534 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.1381G>C (p.G461R) alteration is located in exon 6 (coding exon 6) of the TRMT61B gene. This alteration results from a G to C substitution at nucleotide position 1381, causing the glycine (G) at amino acid position 461 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.81		Gain of MoRF binding (P = 0.0093);
MVP		0.66
MPC		0.49
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.69
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29073203;