NM_001039693.3:c.703C>G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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]

C2orf69 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 53

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039693.3. 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
	TYW5	NM_001039693.3	MANE Select	c.703C>G	p.His235Asp	missense	Exon 8 of 8	NP_001034782.1	A2RUC4-1
	TYW5	NR_004862.2		n.705C>G		non_coding_transcript_exon	Exon 8 of 8
	TYW5	NR_109905.2		n.453C>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYW5	ENST00000354611.9	TSL:1 MANE Select	c.703C>G	p.His235Asp	missense	Exon 8 of 8	ENSP00000346627.4	A2RUC4-1
	TYW5	ENST00000441832.1	TSL:1	n.*230C>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000398447.1	A8KAJ9
	TYW5	ENST00000483328.5	TSL:1	n.*318C>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000420024.1	A8KAJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.7
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
Mutation Taster		=5/95	disease causing

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

Other links and lift over

hg19: chr2-200798035;