1-74752364-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138467.3(TYW3):c.499A>G(p.Ile167Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYW3 NM_138467.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12548906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYW3	NM_138467.3	c.499A>G	p.Ile167Val	missense_variant	5/6	ENST00000370867.8
TYW3	NM_001162916.2	c.400A>G	p.Ile134Val	missense_variant	4/5
TYW3	XM_006710347.3	c.499A>G	p.Ile167Val	missense_variant	5/7
TYW3	NR_027962.2	n.705A>G		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYW3	ENST00000370867.8	c.499A>G	p.Ile167Val	missense_variant	5/6	1	NM_138467.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Apr 26, 2023

The c.499A>G (p.I167V) alteration is located in exon 5 (coding exon 5) of the TYW3 gene. This alteration results from a A to G substitution at nucleotide position 499, causing the isoleucine (I) at amino acid position 167 to be replaced by a valine (V). 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	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.68	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.66	N;N;.;.
REVEL	Benign	0.063
Sift	Benign	0.24	T;T;.;.
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0040	.;B;.;.
Vest4		0.31
MutPred		0.56		.;Gain of phosphorylation at Y166 (P = 0.1951);.;.;
MVP		0.055
MPC		0.093
ClinPred		0.61	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.26

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: chr1-75218048;