13-94590872-A-G

Variant names:

• chr13-94590872-A-G
• rs727502808
• NM_014305.4:c.294T>C
• TGDS p.Phe98Phe

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_ModerateBP7

The NM_014305.4(TGDS):c.294T>C (p.Phe98Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000191 (AC=3) in the gnomAD database across 1,569,018 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000176. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. 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.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TGDS NM_014305.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03
• Publications: 1 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000176 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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.294T>C p.Phe98Phe	synonymous	Exon 4 of 12	Prot: NP_055120.1 UniProt:
	TGDS NM_001304430.2		c.198T>C p.Phe66Phe	synonymous	Exon 4 of 12	Prot: NP_001291359.1
	TGDS NR_130731.2		n.310T>C	non_coding_transcript_exon	Exon 4 of 12	Prot:

TGDS NM_014305.4

MANE Select

HGVSc / HGVSpc.294T>Cp.Phe98Phe

Exon rankExon 4 of 12

synonymous

Prot: NP_055120.1UniProt: O95455

TGDS NM_001304430.2

HGVSc / HGVSpc.198T>Cp.Phe66Phe

Exon rankExon 4 of 12

synonymous

Prot: NP_001291359.1

TGDS NR_130731.2

HGVSc / HGVSpn.310T>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.294T>C p.Phe98Phe	synonymous	Exon 4 of 12	Prot: ENSP00000261296.5 UniProt:
	TGDS ENST00000953437.1		c.294T>C p.Phe98Phe	synonymous	Exon 4 of 12	Prot: ENSP00000623496.1 UniProt:
	TGDS ENST00000921421.1		c.225T>C p.Phe75Phe	synonymous	Exon 3 of 11	Prot: ENSP00000591480.1 UniProt:

TGDS ENST00000261296.7

TSL:1MANE Select

HGVSc / HGVSpc.294T>Cp.Phe98Phe

Exon rankExon 4 of 12

synonymous

Prot: ENSP00000261296.5UniProt: O95455

TGDS ENST00000953437.1

HGVSc / HGVSpc.294T>Cp.Phe98Phe

Exon rankExon 4 of 12

synonymous

Prot: ENSP00000623496.1UniProt: A0ACI8UR48

TGDS ENST00000921421.1

HGVSc / HGVSpc.225T>Cp.Phe75Phe

Exon rankExon 3 of 11

synonymous

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152220	Cov:32
GnomAD4 exome	AF: 7.06e-7	AC:1	Hom:0	AN:1416798	Cov:30
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152220	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:1	Hom:0	AN:16840	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000274	2	73096	0.0000377	5	132704

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.77
GPN-Star LLR	N/A	-3.0
GPN-Star score	N/A	3.0
PhyloP100	Uncertain	4.0

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.12	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

dbSNP: rs727502808;

hg19: chr13-95243126;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar