1-74763946-C-T

Variant names:

• chr1-74763946-C-T
• NM_138467.3:c.613C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138467.3(TYW3):​c.613C>T​(p.His205Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,554 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TYW3 NM_138467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.270

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05935383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW3	NM_138467.3	c.613C>T	p.His205Tyr	missense_variant	Exon 6 of 6	ENST00000370867.8	NP_612476.1
TYW3	NM_001162916.2	c.514C>T	p.His172Tyr	missense_variant	Exon 5 of 5		NP_001156388.1
TYW3	XM_006710347.3	c.613C>T	p.His205Tyr	missense_variant	Exon 6 of 7		XP_006710410.1
TYW3	NR_027962.2	n.819C>T		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW3	ENST00000370867.8	c.613C>T	p.His205Tyr	missense_variant	Exon 6 of 6	1	NM_138467.3	ENSP00000359904.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455554 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723750

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: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.613C>T (p.H205Y) alteration is located in exon 6 (coding exon 6) of the TYW3 gene. This alteration results from a C to T substitution at nucleotide position 613, causing the histidine (H) at amino acid position 205 to be replaced by a tyrosine (Y). 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	0.061
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0038	.;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	.;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.093
Sift	Benign	0.39	T;T;.
Sift4G	Uncertain	0.043	D;D;D
Polyphen		0.0	.;B;.
Vest4		0.088
MutPred		0.19		.;Gain of methylation at K209 (P = 0.0694);.;
MVP		0.22
MPC		0.11
ClinPred		0.054	T
GERP RS		2.4
Varity_R		0.032
gMVP		0.12

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: chr1-75229630;