13-94574874-CAAAA-CA

Variant names:

• chr13-94574874-CAAA-C
• rs748047100
• NM_014305.4:c.983-25_983-23delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014305.4(TGDS):​c.983-25_983-23delTTT variant causes a intron change. The variant allele was found at a frequency of 0.0000439 in 980,096 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000095 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TGDS NM_014305.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.983-25_983-23delTTT		intron	N/A	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.887-25_887-23delTTT		intron	N/A	NP_001291359.1
	TGDS	NR_130731.2		n.995-25_995-23delTTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGDS	ENST00000261296.7	TSL:1 MANE Select	c.983-25_983-23delTTT		intron	N/A	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.953-25_953-23delTTT		intron	N/A	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.914-25_914-23delTTT		intron	N/A	ENSP00000591480.1

Frequencies

GnomAD3 genomes AF: 0.00000950 AC: 1 AN: 105300 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 14 AN: 53648 AF XY: 0.000379

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000403

Gnomad ASJ exome AF: 0.000391

Gnomad EAS exome AF: 0.000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000833

Gnomad OTH exome AF: 0.000707

GnomAD4 exome AF: 0.0000480 AC: 42 AN: 874796 Hom.: 0 AF XY: 0.0000523 AC XY: 23 AN XY: 439820

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

African (AFR) AF: 0.0000548 AC: 1 AN: 18236

American (AMR) AF: 0.0000484 AC: 1 AN: 20680

Ashkenazi Jewish (ASJ) AF: 0.0000616 AC: 1 AN: 16222

East Asian (EAS) AF: 0.000137 AC: 4 AN: 29222

South Asian (SAS) AF: 0.000158 AC: 8 AN: 50628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3026

European-Non Finnish (NFE) AF: 0.0000387 AC: 26 AN: 671302

Other (OTH) AF: 0.0000269 AC: 1 AN: 37118

⚠️ 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: 0.00000950 AC: 1 AN: 105300 Hom.: 0 Cov.: 30 AF XY: 0.0000197 AC XY: 1 AN XY: 50774

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

African (AFR) AF: 0.00 AC: 0 AN: 21856

American (AMR) AF: 0.00 AC: 0 AN: 11592

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4518

South Asian (SAS) AF: 0.00 AC: 0 AN: 3772

European-Finnish (FIN) AF: 0.000162 AC: 1 AN: 6180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52204

Other (OTH) AF: 0.00 AC: 0 AN: 1458

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

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: rs748047100; hg19: chr13-95227128;