chr1-74733362-C-G

Variant names:

• chr1-74733362-C-G
• NM_138467.3:c.118C>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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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]

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.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 6	ENST00000370867.8	NP_612476.1
TYW3	NM_001162916.2	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 5		NP_001156388.1
TYW3	XM_006710347.3	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 7		XP_006710410.1
TYW3	NR_027962.2	n.211C>G		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW3	ENST00000370867.8	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 6	1	NM_138467.3	ENSP00000359904.3
CRYZ	ENST00000417775.5	c.-459G>C		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000399805.1
TYW3	ENST00000457880.6	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 5	2		ENSP00000407025.2
TYW3	ENST00000479111	c.-308C>G		5_prime_UTR_variant	Exon 1 of 7	3		ENSP00000477469.1

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

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;