13-94574874-C-CA

Variant names:

• chr13-94574874-C-CA
• rs748047100
• NM_014305.4:c.983-23dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014305.4(TGDS):​c.983-23dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 928,724 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (41 hom., cov: 30)
  • Exomes 𝑓: 0.055 (12 hom.)
• Consequence: TGDS NM_014305.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 13-94574874-C-CA is Benign according to our data. Variant chr13-94574874-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1261515.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

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.983-23dupT		intron	N/A	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.887-23dupT		intron	N/A	NP_001291359.1
	TGDS	NR_130731.2		n.995-23dupT		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_983-22insT		intron	N/A	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.953-23_953-22insT		intron	N/A	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.914-23_914-22insT		intron	N/A	ENSP00000591480.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 2568 AN: 105244 Hom.: 41 Cov.: 30

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.0289

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0232

Gnomad EAS AF: 0.00398

Gnomad SAS AF: 0.00770

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0233

GnomAD2 exomes AF: 0.0926 AC: 4970 AN: 53648 AF XY: 0.0906

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0989

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.0641

Gnomad NFE exome AF: 0.0820

Gnomad OTH exome AF: 0.0912

GnomAD4 exome AF: 0.0550 AC: 45278 AN: 823458 Hom.: 12 Cov.: 11 AF XY: 0.0553 AC XY: 22840 AN XY: 412856

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

African (AFR) AF: 0.0619 AC: 1096 AN: 17694

American (AMR) AF: 0.0652 AC: 1254 AN: 19228

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 1033 AN: 14894

East Asian (EAS) AF: 0.0662 AC: 1635 AN: 24710

South Asian (SAS) AF: 0.0640 AC: 3024 AN: 47242

European-Finnish (FIN) AF: 0.0443 AC: 1134 AN: 25622

Middle Eastern (MID) AF: 0.0705 AC: 200 AN: 2836

European-Non Finnish (NFE) AF: 0.0533 AC: 33912 AN: 636680

Other (OTH) AF: 0.0576 AC: 1990 AN: 34552

⚠️ 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: 0.0245 AC: 2577 AN: 105266 Hom.: 41 Cov.: 30 AF XY: 0.0236 AC XY: 1201 AN XY: 50786

African (AFR) AF: 0.0714 AC: 1565 AN: 21914

American (AMR) AF: 0.0119 AC: 138 AN: 11606

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 64 AN: 2758

East Asian (EAS) AF: 0.00400 AC: 18 AN: 4500

South Asian (SAS) AF: 0.00801 AC: 30 AN: 3746

European-Finnish (FIN) AF: 0.00438 AC: 27 AN: 6168

Middle Eastern (MID) AF: 0.0425 AC: 9 AN: 212

European-Non Finnish (NFE) AF: 0.0129 AC: 671 AN: 52170

Other (OTH) AF: 0.0232 AC: 34 AN: 1466

Alfa AF: 0.00210 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs748047100; hg19: chr13-95227128;