11-61339293-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015533.4(TKFC):c.344G>A(p.Arg115Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,852 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: TKFC NM_015533.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.85

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025957704).
• BP6: Variant 11-61339293-G-A is Benign according to our data. Variant chr11-61339293-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2578659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TKFC	NM_015533.4	c.344G>A	p.Arg115Gln	missense_variant	5/18	ENST00000394900.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TKFC	ENST00000394900.8	c.344G>A	p.Arg115Gln	missense_variant	5/18	1	NM_015533.4	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152248 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00252 AC: 631 AN: 250624 Hom.: 3 AF XY: 0.00245 AC XY: 332 AN XY: 135622

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00407 AC: 5947 AN: 1461486 Hom.: 21 Cov.: 61 AF XY: 0.00401 AC XY: 2919 AN XY: 727046

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.00333

Gnomad4 NFE exome AF: 0.00476

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152366 Hom.: 1 Cov.: 34 AF XY: 0.00272 AC XY: 203 AN XY: 74506

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00374 Hom.: 1

Bravo AF: 0.00264

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00273

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

TKFC: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;T;D
Polyphen		1.0	D;.;.
Vest4		0.89
MVP		0.60
MPC		0.67
ClinPred		0.083	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144902033; hg19: chr11-61106765; COSMIC: COSV101204247; COSMIC: COSV101204247;