rs3812475

chr8-124451009-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017956.4(TRMT12):c.82T>C(p.Trp28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,798 control chromosomes in the GnomAD database, including 201,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W28S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.55 (23838 hom., cov: 31)
  • Exomes 𝑓: 0.49 (178024 hom.)
• Consequence: TRMT12 NM_017956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2153973E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRMT12	NM_017956.4	c.82T>C	p.Trp28Arg	missense_variant	1/1	ENST00000328599.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRMT12	ENST00000328599.4	c.82T>C	p.Trp28Arg	missense_variant	1/1		NM_017956.4	P1
TRMT12	ENST00000521443.1	n.190T>C		non_coding_transcript_exon_variant	1/2	4
TRMT12	ENST00000522518.1	c.82T>C	p.Trp28Arg	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83225 AN: 151880 Hom.: 23790 Cov.: 31

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.537

GnomAD3 exomes AF: 0.503 AC: 126448 AN: 251402 Hom.: 32511 AF XY: 0.502 AC XY: 68250 AN XY: 135872

Gnomad AFR exome AF: 0.720

Gnomad AMR exome AF: 0.452

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.481

Gnomad OTH exome AF: 0.502

GnomAD4 exome AF: 0.491 AC: 717387 AN: 1461798 Hom.: 178024 Cov.: 51 AF XY: 0.491 AC XY: 357381 AN XY: 727206

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.478

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.548 AC: 83316 AN: 152000 Hom.: 23838 Cov.: 31 AF XY: 0.548 AC XY: 40718 AN XY: 74278

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.456

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.536

Alfa AF: 0.495 Hom.: 48458

Bravo AF: 0.554

TwinsUK AF: 0.463 AC: 1716

ALSPAC AF: 0.474 AC: 1826

ESP6500AA AF: 0.695 AC: 3061

ESP6500EA AF: 0.472 AC: 4059

ExAC AF: 0.512 AC: 62192

Asia WGS AF: 0.528 AC: 1833 AN: 3478

EpiCase AF: 0.490

EpiControl AF: 0.494

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.73
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.4	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.080
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.37		Gain of disorder (P = 0.004);
MPC		0.40
ClinPred		0.0027	T
GERP RS		5.2
Varity_R		0.071
gMVP		0.25

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: rs3812475; hg19: chr8-125463250; COSMIC: COSV60776700;