13-94576404-T-A

Variant names:

• chr13-94576404-T-A
• rs724160005
• NM_014305.4:c.892A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_014305.4(TGDS):​c.892A>T​(p.Asn298Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N298D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGDS NM_014305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15
• Publications: 3 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-94576404-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162460.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.29997 (below the threshold of 3.09). Trascript score misZ: 0.81559 (below the threshold of 3.09). GenCC associations: The gene is linked to Catel-Manzke syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014305.4. 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
	TGDS	NM_014305.4	MANE Select	c.892A>T	p.Asn298Tyr	missense	Exon 11 of 12	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.796A>T	p.Asn266Tyr	missense	Exon 11 of 12	NP_001291359.1
	TGDS	NR_130731.2		n.904A>T		non_coding_transcript_exon	Exon 11 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGDS	ENST00000261296.7	TSL:1 MANE Select	c.892A>T	p.Asn298Tyr	missense	Exon 11 of 12	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.862A>T	p.Asn288Tyr	missense	Exon 11 of 12	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.823A>T	p.Asn275Tyr	missense	Exon 10 of 11	ENSP00000591480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.66		Gain of phosphorylation at N298 (P = 0.0349)
MVP		0.92
MPC		0.66
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.68
Mutation Taster		=66/34	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: rs724160005; hg19: chr13-95228658;