Genetic Variant TYW1B:p.Val172Ile (chr7-72807275-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145440.3(TYW1B):c.514G>A(p.Val172Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000849 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

TYW1B
NM_001145440.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Variant links:

Genes affected

TYW1B (HGNC:33908): (tRNA-yW synthesizing protein 1 homolog B) Wybutosine is a hypermodified guanosine found in phenylalanine tRNA. Wybutosine functions to stabilize codon-anticodon interactions during ribosome decoding and therefore supports the maintenance of the reading frame. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. The human genome contains two closely related genes that putatively function in wybutosine synthesis. The open reading frame of this locus is disrupted in some individuals. Thus, this locus appears to be an evolving pseudogene, but may still be functional in some members of the population. [provided by RefSeq, Apr 2014]

TYW1B links:

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ACMG classification

Classification made for transcript

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=0.043177485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW1B	NM_001145440.3 link	c.514G>A	p.Val172Ile	missense_variant	Exon 5 of 14	ENST00000620995.5	NP_001138912.2	Q6NUM6-1
TYW1B	NM_001412179.1 link	c.514G>A	p.Val172Ile	missense_variant	Exon 5 of 12		NP_001399108.1
TYW1B	NM_001412180.1 link	c.514G>A	p.Val172Ile	missense_variant	Exon 5 of 11		NP_001399109.1
TYW1B	NM_001412181.1 link	c.514G>A	p.Val172Ile	missense_variant	Exon 5 of 5		NP_001399110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TYW1B	ENST00000620995.5 link	c.514G>A	p.Val172Ile	missense_variant	Exon 5 of 14	1	NM_001145440.3	ENSP00000482502.1	Q6NUM6-1
TYW1B	ENST00000612372.4 link	c.238-4753G>A		intron_variant	Intron 3 of 11	1		ENSP00000480534.1	A0A087WWV6
TYW1B	ENST00000610600.1 link	c.319G>A	p.Val107Ile	missense_variant	Exon 4 of 8	2		ENSP00000484480.1	A0A087X1V1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251460

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>A (p.V172I) alteration is located in exon 5 (coding exon 5) of the TYW1B gene. This alteration results from a G to A substitution at nucleotide position 514, causing the valine (V) at amino acid position 172 to be replaced by an isoleucine (I). 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

0.093

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.017

T;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0020

MetaRNN

Benign

0.043

T;T

PrimateAI

Uncertain

0.60

Sift4G

Benign

0.18

T;T

Polyphen

0.88

P;.

Vest4

0.34

MVP

0.34

GERP RS

2.6

Varity_R

0.057

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over