13-94574874-CAAAA-CAAAAAA

Variant names:

• chr13-94574874-C-CAA
• rs748047100
• NM_014305.4:c.983-24_983-23dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014305.4(TGDS):​c.983-24_983-23dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 978,304 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: TGDS NM_014305.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00588 (619/105314) while in subpopulation AFR AF = 0.0261 (572/21914). AF 95% confidence interval is 0.0243. There are 5 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.983-24_983-23dupTT		intron	N/A	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.887-24_887-23dupTT		intron	N/A	NP_001291359.1
	TGDS	NR_130731.2		n.995-24_995-23dupTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGDS	ENST00000261296.7	TSL:1 MANE Select	c.983-23_983-22insTT		intron	N/A	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.953-23_953-22insTT		intron	N/A	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.914-23_914-22insTT		intron	N/A	ENSP00000591480.1

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 617 AN: 105292 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000383

Gnomad OTH AF: 0.00481

GnomAD2 exomes AF: 0.00211 AC: 113 AN: 53648 AF XY: 0.00162

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.000188

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.000749 AC: 654 AN: 872990 Hom.: 0 Cov.: 11 AF XY: 0.000695 AC XY: 305 AN XY: 438886

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0115 AC: 209 AN: 18176

American (AMR) AF: 0.00111 AC: 23 AN: 20644

Ashkenazi Jewish (ASJ) AF: 0.000618 AC: 10 AN: 16180

East Asian (EAS) AF: 0.0000686 AC: 2 AN: 29158

South Asian (SAS) AF: 0.000435 AC: 22 AN: 50534

European-Finnish (FIN) AF: 0.000388 AC: 11 AN: 28342

Middle Eastern (MID) AF: 0.000331 AC: 1 AN: 3018

European-Non Finnish (NFE) AF: 0.000470 AC: 315 AN: 669906

Other (OTH) AF: 0.00165 AC: 61 AN: 37032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00588 AC: 619 AN: 105314 Hom.: 5 Cov.: 30 AF XY: 0.00594 AC XY: 302 AN XY: 50814

African (AFR) AF: 0.0261 AC: 572 AN: 21914

American (AMR) AF: 0.00327 AC: 38 AN: 11610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2760

East Asian (EAS) AF: 0.00 AC: 0 AN: 4500

South Asian (SAS) AF: 0.00 AC: 0 AN: 3750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000383 AC: 2 AN: 52196

Other (OTH) AF: 0.00478 AC: 7 AN: 1464

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748047100; hg19: chr13-95227128;