1-74736560-G-A

Variant names:

• chr1-74736560-G-A
• rs778991657
• NM_138467.3:c.193G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138467.3(TYW3):​c.193G>A​(p.Val65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V65F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TYW3 NM_138467.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.832
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067701966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYW3	NM_138467.3	MANE Select	c.193G>A	p.Val65Ile	missense	Exon 2 of 6	NP_612476.1	Q6IPR3-1
	TYW3	NM_001162916.2		c.193G>A	p.Val65Ile	missense	Exon 2 of 5	NP_001156388.1	Q6IPR3-2
	TYW3	NR_027962.2		n.399G>A		non_coding_transcript_exon	Exon 2 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYW3	ENST00000370867.8	TSL:1 MANE Select	c.193G>A	p.Val65Ile	missense	Exon 2 of 6	ENSP00000359904.3	Q6IPR3-1
	TYW3	ENST00000922907.1		c.193G>A	p.Val65Ile	missense	Exon 2 of 7	ENSP00000592966.1
	TYW3	ENST00000922906.1		c.193G>A	p.Val65Ile	missense	Exon 2 of 6	ENSP00000592965.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448692 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720158

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.0000229 AC: 1 AN: 43744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.00 AC: 0 AN: 82606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105528

Other (OTH) AF: 0.00 AC: 0 AN: 59756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		0.83
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.020
Sift	Benign	0.51	T
Sift4G	Benign	0.55	T
Polyphen		0.0040	B
Vest4		0.091
MutPred		0.51		Loss of ubiquitination at K67 (P = 0.0997)
MVP		0.23
MPC		0.079
ClinPred		0.16	T
GERP RS		1.3
PromoterAI		-0.0081	Neutral
Varity_R		0.017
gMVP		0.12
Mutation Taster		=293/7	polymorphism

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

Other links and lift over

dbSNP: rs778991657; hg19: chr1-75202244;