chr1-74733362-C-G

Variant summary

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

The NM_138467.3(TYW3):​c.118C>G​(p.Arg40Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TYW3
NM_138467.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71
Variant links:
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]
CRYZ (HGNC:2419): (crystallin zeta) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. The former class is also called phylogenetically-restricted crystallins. This gene encodes a taxon-specific crystallin protein which has NADPH-dependent quinone reductase activity distinct from other known quinone reductases. It lacks alcohol dehydrogenase activity although by similarity it is considered a member of the zinc-containing alcohol dehydrogenase family. Unlike other mammalian species, in humans, lens expression is low. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One pseudogene is known to exist. [provided by RefSeq, Sep 2008]

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ACMG classification

Classification made for transcript

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
TYW3NM_138467.3 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 6 ENST00000370867.8 NP_612476.1 Q6IPR3-1
TYW3NM_001162916.2 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 5 NP_001156388.1 Q6IPR3-2Q96GE7
TYW3XM_006710347.3 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 7 XP_006710410.1 Q6IPR3-1
TYW3NR_027962.2 linkn.211C>G non_coding_transcript_exon_variant Exon 1 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TYW3ENST00000370867.8 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 6 1 NM_138467.3 ENSP00000359904.3 Q6IPR3-1
CRYZENST00000417775.5 linkc.-459G>C 5_prime_UTR_variant Exon 1 of 10 1 ENSP00000399805.1 Q08257-1
TYW3ENST00000457880.6 linkc.118C>G p.Arg40Gly missense_variant Exon 1 of 5 2 ENSP00000407025.2 Q6IPR3-2
TYW3ENST00000479111 linkc.-308C>G 5_prime_UTR_variant Exon 1 of 7 3 ENSP00000477469.1 V9GZ67

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 16, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.118C>G (p.R40G) alteration is located in exon 1 (coding exon 1) of the TYW3 gene. This alteration results from a C to G substitution at nucleotide position 118, causing the arginine (R) at amino acid position 40 to be replaced by a glycine (G). 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
0.16
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.025
.;T
Eigen
Benign
0.0097
Eigen_PC
Benign
-0.086
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.16
Sift
Uncertain
0.027
D;D
Sift4G
Benign
0.10
T;T
Polyphen
0.79
.;P
Vest4
0.52
MutPred
0.49
Loss of stability (P = 0.0206);Loss of stability (P = 0.0206);
MVP
0.33
MPC
0.19
ClinPred
0.97
D
GERP RS
4.8
Varity_R
0.53
gMVP
0.39

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: chr1-75199046; API