chr8-124451009-T-C

Variant names:

• chr8-124451009-T-C
• rs3812475
• NM_017956.4:c.82T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017956.4(TYW2):​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. 15/21 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 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: TYW2 NM_017956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 58 publications found

Genes affected

TYW2 (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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TYW2	NM_017956.4	c.82T>C	p.Trp28Arg	missense_variant	Exon 1 of 1	ENST00000328599.4	NP_060426.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRMT12	ENST00000328599.4	c.82T>C	p.Trp28Arg	missense_variant	Exon 1 of 1	6	NM_017956.4	ENSP00000329858.3
TRMT12	ENST00000521443.1	n.190T>C		non_coding_transcript_exon_variant	Exon 1 of 2	4
TRMT12	ENST00000522518.1	n.82T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000429771.1

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

GnomAD2 exomes AF: 0.503 AC: 126448 AN: 251402 AF XY: 0.502

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 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

African (AFR) AF: 0.729 AC: 24420 AN: 33480

American (AMR) AF: 0.460 AC: 20556 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13287 AN: 26136

East Asian (EAS) AF: 0.459 AC: 18232 AN: 39700

South Asian (SAS) AF: 0.541 AC: 46626 AN: 86244

European-Finnish (FIN) AF: 0.522 AC: 27867 AN: 53418

Middle Eastern (MID) AF: 0.579 AC: 3339 AN: 5768

European-Non Finnish (NFE) AF: 0.478 AC: 531552 AN: 1111936

Other (OTH) AF: 0.522 AC: 31508 AN: 60396

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

African (AFR) AF: 0.719 AC: 29791 AN: 41450

American (AMR) AF: 0.478 AC: 7291 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1746 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2357 AN: 5168

South Asian (SAS) AF: 0.544 AC: 2613 AN: 4806

European-Finnish (FIN) AF: 0.520 AC: 5493 AN: 10558

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32365 AN: 67970

Other (OTH) AF: 0.536 AC: 1129 AN: 2106

Alfa AF: 0.500 Hom.: 95280

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
PhyloP100		0.55
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
PromoterAI		0.0074	Neutral
Varity_R		0.071
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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