7-72777436-C-T

Variant names:

• chr7-72777436-C-T
• rs1554470748
• NM_001145440.3:c.944G>A

Variant summary

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

The NM_001145440.3(TYW1B):​c.944G>A​(p.Arg315Gln) 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. 8/13 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: TYW1B NM_001145440.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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]

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=0.26031768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW1B	NM_001145440.3	c.944G>A	p.Arg315Gln	missense_variant	Exon 7 of 14	ENST00000620995.5	NP_001138912.2
TYW1B	NM_001412179.1	c.944G>A	p.Arg315Gln	missense_variant	Exon 7 of 12		NP_001399108.1
TYW1B	NM_001412180.1	c.944G>A	p.Arg315Gln	missense_variant	Exon 7 of 11		NP_001399109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW1B	ENST00000620995.5	c.944G>A	p.Arg315Gln	missense_variant	Exon 7 of 14	1	NM_001145440.3	ENSP00000482502.1
TYW1B	ENST00000612372.4	c.458G>A	p.Arg153Gln	missense_variant	Exon 5 of 12	1		ENSP00000480534.1
TYW1B	ENST00000610600.1	c.749G>A	p.Arg250Gln	missense_variant	Exon 6 of 8	2		ENSP00000484480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.944G>A (p.R315Q) alteration is located in exon 7 (coding exon 7) of the TYW1B gene. This alteration results from a G to A substitution at nucleotide position 944, causing the arginine (R) at amino acid position 315 to be replaced by a glutamine (Q). 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	0.091
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.81
DEOGEN2	Benign	0.12	.;T;.
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.26	T;T;T
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.074	T;D;T
Polyphen		0.58	.;P;.
Vest4		0.25
MVP		0.37
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.58

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

Other links and lift over

dbSNP: rs1554470748; hg19: chr7-72242447; COSMIC: COSV71264219;