11-61341502-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015533.4(TKFC):c.553G>A(p.Ala185Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.957 in 1,555,306 control chromosomes in the GnomAD database, including 722,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.84 (57530 hom., cov: 33)
  • Exomes 𝑓: 0.97 (665180 hom.)
• Consequence: TKFC NM_015533.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.866

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3130717E-6).
• BP6: Variant 11-61341502-G-A is Benign according to our data. Variant chr11-61341502-G-A is described in ClinVar as [Benign]. Clinvar id is 1255451.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TKFC	NM_015533.4	c.553G>A	p.Ala185Thr	missense_variant	6/18	ENST00000394900.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TKFC	ENST00000394900.8	c.553G>A	p.Ala185Thr	missense_variant	6/18	1	NM_015533.4	P1
TKFC	ENST00000529479.5	c.550G>A	p.Ala184Thr	missense_variant	4/16	1
DDB1	ENST00000540166.5	c.-166+866C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127770 AN: 152070 Hom.: 57536 Cov.: 33

Gnomad AFR AF: 0.480

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.992

Gnomad OTH AF: 0.884

GnomAD3 exomes AF: 0.938 AC: 152342 AN: 162394 Hom.: 72744 AF XY: 0.942 AC XY: 80664 AN XY: 85626

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.971

Gnomad ASJ exome AF: 0.989

Gnomad EAS exome AF: 0.966

Gnomad SAS exome AF: 0.874

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.991

Gnomad OTH exome AF: 0.964

GnomAD4 exome AF: 0.970 AC: 1360701 AN: 1403118 Hom.: 665180 Cov.: 58 AF XY: 0.968 AC XY: 670564 AN XY: 692450

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.967

Gnomad4 ASJ exome AF: 0.988

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.876

Gnomad4 FIN exome AF: 0.985

Gnomad4 NFE exome AF: 0.993

Gnomad4 OTH exome AF: 0.941

GnomAD4 genome AF: 0.840 AC: 127786 AN: 152188 Hom.: 57530 Cov.: 33 AF XY: 0.842 AC XY: 62614 AN XY: 74406

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.942

Gnomad4 ASJ AF: 0.989

Gnomad4 EAS AF: 0.965

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.986

Gnomad4 NFE AF: 0.992

Gnomad4 OTH AF: 0.878

Alfa AF: 0.967 Hom.: 148336

Bravo AF: 0.825

TwinsUK AF: 0.994 AC: 3685

ALSPAC AF: 0.992 AC: 3824

ESP6500AA AF: 0.512 AC: 2246

ESP6500EA AF: 0.991 AC: 8463

ExAC AF: 0.906 AC: 91974

Asia WGS AF: 0.842 AC: 2927 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Triokinase and FMN cyclase deficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.065
Sift	Benign	0.51	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.35	B;.
Vest4		0.035
MPC		0.14
ClinPred		0.0063	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2260655; hg19: chr11-61108974; COSMIC: COSV67523931; COSMIC: COSV67523931;