NM_014305.4:c.269A>G

Variant names:

• chr13-94590897-T-C
• rs724160004
• NM_014305.4:c.269A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_014305.4(TGDS):​c.269A>G​(p.Glu90Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,424,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TGDS NM_014305.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.80
• Publications: 2 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.885
• PP5: Variant 13-94590897-T-C is Pathogenic according to our data. Variant chr13-94590897-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162457.Status of the report is no_assertion_criteria_provided, 0 stars.

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.269A>G	p.Glu90Gly	missense	Exon 4 of 12	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.173A>G	p.Glu58Gly	missense	Exon 4 of 12	NP_001291359.1
	TGDS	NR_130731.2		n.285A>G		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGDS	ENST00000261296.7	TSL:1 MANE Select	c.269A>G	p.Glu90Gly	missense	Exon 4 of 12	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.269A>G	p.Glu90Gly	missense	Exon 4 of 12	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.200A>G	p.Glu67Gly	missense	Exon 3 of 11	ENSP00000591480.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000232 AC: 5 AN: 215774 AF XY: 0.0000255

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000429

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000386

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1424284 Hom.: 0 Cov.: 30 AF XY: 0.0000184 AC XY: 13 AN XY: 707848

African (AFR) AF: 0.00 AC: 0 AN: 30772

American (AMR) AF: 0.0000294 AC: 1 AN: 34028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 37684

South Asian (SAS) AF: 0.00 AC: 0 AN: 78382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1100628

Other (OTH) AF: 0.0000170 AC: 1 AN: 58940

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Catel-Manzke syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.52		Loss of stability (P = 0.0473)
MVP		0.92
MPC		0.46
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.69
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 0

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

Other links and lift over

dbSNP: rs724160004; hg19: chr13-95243151;