NM_014305.4:c.292T>C

Variant names:

• chr13-94590874-A-G
• NM_014305.4:c.292T>C
• TGDS p.Phe98Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO7_Moderate

The NM_014305.4(TGDS):c.292T>C (p.Phe98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGDS NM_014305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• Publications: 0 publications found

Genes affected

TGDS (HGNC:20324): (TDP-glucose 4,6-dehydratase) The protein encoded by this gene is a member of the short-chain dehydrogenases/reductases (SDR) superfamily, and is thought to contain a nicotinamide adenine dinucleotide (NAD) binding domain. This large SDR family of enzymes is involved in the metabolism of a variety of compounds, including prostaglandins, retinoids, lipids, steroid hormones, and xenobiotics. Mutations in this gene have been associated with Catel-Manzke syndrome, which is characterized by Pierre Robin sequence, and radial deviation of the index finger due to the presence of an accessory bone between the index finger and its proximal phalanx. Pierre Robin sequence is defined by an undersized jaw, backwards displacement of the tongue base that causes an obstruction of the airways, and can also be associated with a cleft palate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

TGDS Gene-Disease associations (from GenCC):

• Catel-Manzke syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; Single-residue UniProt domain — benign variants: 0 (OR vs. background: 15.0); ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014305.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGDS NM_014305.4	MANE Select	c.292T>C p.Phe98Leu	missense	Exon 4 of 12	Prot: NP_055120.1 UniProt:
	TGDS NM_001304430.2		c.196T>C p.Phe66Leu	missense	Exon 4 of 12	Prot: NP_001291359.1
	TGDS NR_130731.2		n.308T>C	non_coding_transcript_exon	Exon 4 of 12	Prot:

TGDS NM_014305.4

MANE Select

HGVSc / HGVSpc.292T>Cp.Phe98Leu

Exon rankExon 4 of 12

missense

Prot: NP_055120.1UniProt: O95455

TGDS NM_001304430.2

HGVSc / HGVSpc.196T>Cp.Phe66Leu

Exon rankExon 4 of 12

missense

Prot: NP_001291359.1

TGDS NR_130731.2

HGVSc / HGVSpn.308T>C

Exon rankExon 4 of 12

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGDS ENST00000261296.7	TSL:1MANE Select	c.292T>C p.Phe98Leu	missense	Exon 4 of 12	Prot: ENSP00000261296.5 UniProt:
	TGDS ENST00000953437.1		c.292T>C p.Phe98Leu	missense	Exon 4 of 12	Prot: ENSP00000623496.1 UniProt:
	TGDS ENST00000921421.1		c.223T>C p.Phe75Leu	missense	Exon 3 of 11	Prot: ENSP00000591480.1 UniProt:

TGDS ENST00000261296.7

TSL:1MANE Select

HGVSc / HGVSpc.292T>Cp.Phe98Leu

Exon rankExon 4 of 12

missense

Prot: ENSP00000261296.5UniProt: O95455

TGDS ENST00000953437.1

HGVSc / HGVSpc.292T>Cp.Phe98Leu

Exon rankExon 4 of 12

missense

Prot: ENSP00000623496.1UniProt: A0ACI8UR48

TGDS ENST00000921421.1

HGVSc / HGVSpc.223T>Cp.Phe75Leu

Exon rankExon 3 of 11

missense

Prot: ENSP00000591480.1UniProt: A0ACI8T2I5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.22
Eigen_PC	Benign	0.026
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.87
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.31	T
Mutation Taster	N/A	38/62	disease causing
MutationAssessor	Benign	0.35	N
PhyloP100	Uncertain	6.7
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.78
Sift	Benign	0.097	T
Sift4G	Benign	0.13	T
Varity_R	N/A	0.53
VESM-3B	Benign	-7.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr13-95243128;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar