2-199933312-G-C

Variant names:

• chr2-199933312-G-C
• NM_001039693.3:c.703C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001039693.3(TYW5):​c.703C>G​(p.His235Asp) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYW5 NM_001039693.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.67

Genes affected

TYW5 (HGNC:26754): (tRNA-yW synthesizing protein 5) Enables several functions, including iron ion binding activity; protein homodimerization activity; and tRNAPhe (7-(3-amino-3-carboxypropyl)wyosine37-C2)-hydroxylase activity. Involved in wybutosine biosynthetic process. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

C2orf69 (HGNC:26799): (chromosome 2 open reading frame 69) Involved in oxidative phosphorylation. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity TYW5_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYW5	NM_001039693.3	c.703C>G	p.His235Asp	missense_variant	Exon 8 of 8	ENST00000354611.9	NP_001034782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYW5	ENST00000354611.9	c.703C>G	p.His235Asp	missense_variant	Exon 8 of 8	1	NM_001039693.3	ENSP00000346627.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703C>G (p.H235D) alteration is located in exon 8 (coding exon 8) of the TYW5 gene. This alteration results from a C to G substitution at nucleotide position 703, causing the histidine (H) at amino acid position 235 to be replaced by an aspartic acid (D). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.89		Loss of sheet (P = 0.1398);
MVP		0.63
MPC		0.34
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-200798035;