8-124452110-T-C

Position:

• chr8-124452110-T-C

Variant summary

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

The NM_017956.4(TRMT12):​c.1183T>C​(p.Trp395Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRMT12 NM_017956.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

Genes affected

TRMT12 (HGNC:26091): (tRNA methyltransferase 12 homolog) Wybutosine (yW) is a hypermodified guanosine at the 3-prime position adjacent to the anticodon of phenylalanine tRNA that stabilizes codon-anticodon interactions during decoding on the ribosome. TRMT12 is the human homolog of a yeast gene essential for yW synthesis (Noma and Suzuki, 2006).[supplied by OMIM, Mar 2008]

TRMT12 (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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRMT12	NM_017956.4	c.1183T>C	p.Trp395Arg	missense_variant	1/1	ENST00000328599.4	NP_060426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRMT12	ENST00000328599.4	c.1183T>C	p.Trp395Arg	missense_variant	1/1	6	NM_017956.4	ENSP00000329858.3
TRMT12	ENST00000521443.1	n.438+853T>C		intron_variant		4
TRMT12	ENST00000522518.1	n.331-42T>C		intron_variant		3		ENSP00000429771.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Jul 14, 2022

The c.1183T>C (p.W395R) alteration is located in exon 1 (coding exon 1) of the TRMT12 gene. This alteration results from a T to C substitution at nucleotide position 1183, causing the tryptophan (W) at amino acid position 395 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.51		Gain of disorder (P = 0.0064);
MVP		0.61
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr8-125464351;