11-61341833-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015533.4(TKFC):c.576G>A(p.Gly192=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,880 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (15 hom., cov: 32)
  • Exomes 𝑓: 0.013 (154 hom.)
• Consequence: TKFC NM_015533.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.476

Genes affected

TKFC (HGNC:24552): (triokinase and FMN cyclase) This gene is a member of the family of dihydroxyacetone kinases, which have a protein structure distinct from other kinases. The product of this gene phosphorylates dihydroxyacetone, and also catalyzes the formation of riboflavin 4',5'-phosphate (aka cyclin FMN) from FAD. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2017]

DDB1 (HGNC:2717): (damage specific DNA binding protein 1) The protein encoded by this gene is the large subunit (p127) of the heterodimeric DNA damage-binding (DDB) complex while another protein (p48) forms the small subunit. This protein complex functions in nucleotide-excision repair and binds to DNA following UV damage. Defective activity of this complex causes the repair defect in patients with xeroderma pigmentosum complementation group E (XPE) - an autosomal recessive disorder characterized by photosensitivity and early onset of carcinomas. However, it remains for mutation analysis to demonstrate whether the defect in XPE patients is in this gene or the gene encoding the small subunit. In addition, Best vitelliform mascular dystrophy is mapped to the same region as this gene on 11q, but no sequence alternations of this gene are demonstrated in Best disease patients. The protein encoded by this gene also functions as an adaptor molecule for the cullin 4 (CUL4) ubiquitin E3 ligase complex by facilitating the binding of substrates to this complex and the ubiquitination of proteins. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-61341833-G-A is Benign according to our data. Variant chr11-61341833-G-A is described in ClinVar as [Benign]. Clinvar id is 2641824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.476 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0128 (18640/1461662) while in subpopulation NFE AF= 0.0158 (17526/1111842). AF 95% confidence interval is 0.0156. There are 154 homozygotes in gnomad4_exome. There are 8998 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TKFC	NM_015533.4	c.576G>A	p.Gly192=	synonymous_variant	7/18	ENST00000394900.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TKFC	ENST00000394900.8	c.576G>A	p.Gly192=	synonymous_variant	7/18	1	NM_015533.4	P1
TKFC	ENST00000529479.5	c.573G>A	p.Gly191=	synonymous_variant	5/16	1
TKFC	ENST00000533853.1	n.159G>A		non_coding_transcript_exon_variant	1/3	3
DDB1	ENST00000540166.5	c.-166+535C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1330 AN: 152100 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.00779 AC: 1957 AN: 251284 Hom.: 18 AF XY: 0.00762 AC XY: 1035 AN XY: 135814

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.0128 AC: 18640 AN: 1461662 Hom.: 154 Cov.: 32 AF XY: 0.0124 AC XY: 8998 AN XY: 727160

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00509

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.00815

GnomAD4 genome AF: 0.00874 AC: 1331 AN: 152218 Hom.: 15 Cov.: 32 AF XY: 0.00814 AC XY: 606 AN XY: 74428

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.0115 Hom.: 5

Bravo AF: 0.00846

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

TKFC: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.5
Dann	Benign	0.84
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		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

Publications

LitVar

Other links and lift over

dbSNP: rs117064389; hg19: chr11-61109305;