chr7-67098541-G-T

Variant names:

• chr7-67098541-G-T
• rs2261015
• NM_018264.4:c.1385G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018264.4(TYW1):​c.1385G>T​(p.Gly462Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYW1 NM_018264.4 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.30
• Publications: 4 publications found

Genes affected

TYW1 (HGNC:25598): (tRNA-yW synthesizing protein 1 homolog) Wybutosine (yW) is a hypermodified guanosine found in phenylalanine tRNA adjacent to the anticodon that stabilizes codon-anticodon interactions in the ribosome. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW1	NM_018264.4	c.1385G>T	p.Gly462Val	missense_variant, splice_region_variant	Exon 12 of 16	ENST00000359626.10	NP_060734.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW1	ENST00000359626.10	c.1385G>T	p.Gly462Val	missense_variant, splice_region_variant	Exon 12 of 16	1	NM_018264.4	ENSP00000352645.5
TYW1	ENST00000361660.8	n.*177G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 15	1		ENSP00000354795.4
TYW1	ENST00000361660.8	n.*177G>T		3_prime_UTR_variant	Exon 11 of 15	1		ENSP00000354795.4
TYW1	ENST00000495971.1	n.377G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0156 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.6	H;.
PhyloP100		8.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.2	D;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.86
MVP		0.80
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.93
gMVP		0.82
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2261015; hg19: chr7-66563528; COSMIC: COSV62751153;