1-74738762-C-T

Variant names:

• chr1-74738762-C-T
• rs755560668
• NM_138467.3:c.328C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138467.3(TYW3):​c.328C>T​(p.Arg110*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TYW3 NM_138467.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

Genes affected

TYW3 (HGNC:24757): (tRNA-yW synthesizing protein 3 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. TYW3 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW3	NM_138467.3	c.328C>T	p.Arg110*	stop_gained	Exon 3 of 6	ENST00000370867.8	NP_612476.1
TYW3	XM_006710347.3	c.328C>T	p.Arg110*	stop_gained	Exon 3 of 7		XP_006710410.1
TYW3	NM_001162916.2	c.255+2140C>T		intron_variant	Intron 2 of 4		NP_001156388.1
TYW3	NR_027962.2	n.534C>T		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW3	ENST00000370867.8	c.328C>T	p.Arg110*	stop_gained	Exon 3 of 6	1	NM_138467.3	ENSP00000359904.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250932 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458120 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725088

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.22
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 26

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

Publications

LitVar

Other links and lift over

dbSNP: rs755560668; hg19: chr1-75204446;