1-74738719-T-C

Variant names:

• chr1-74738719-T-C
• rs145813190
• NM_138467.3:c.285T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_138467.3(TYW3):​c.285T>C​(p.Asp95Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TYW3 NM_138467.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.652
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=0.652 with no splicing effect.

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.285T>C	p.Asp95Asp	synonymous	Exon 3 of 6	NP_612476.1	Q6IPR3-1
	TYW3	NM_001162916.2		c.255+2097T>C		intron	N/A	NP_001156388.1	Q6IPR3-2
	TYW3	NR_027962.2		n.491T>C		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYW3	ENST00000370867.8	TSL:1 MANE Select	c.285T>C	p.Asp95Asp	synonymous	Exon 3 of 6	ENSP00000359904.3	Q6IPR3-1
	TYW3	ENST00000922907.1		c.285T>C	p.Asp95Asp	synonymous	Exon 3 of 7	ENSP00000592966.1
	TYW3	ENST00000905124.1		c.285T>C	p.Asp95Asp	synonymous	Exon 3 of 7	ENSP00000575183.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457296 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724850

⚠️ 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: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108588

Other (OTH) AF: 0.00 AC: 0 AN: 60174

⚠️ 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: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.2
DANN	Benign	0.33
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=297/3	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: rs145813190; hg19: chr1-75204403;