rs149026556

Variant names:

• chr11-61339313-C-G
• rs149026556
• NM_015533.4:c.364C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-61339313-C-G
• chr11-61339313-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015533.4(TKFC):​c.364C>G​(p.Arg122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TKFC NM_015533.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

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]

DDB1 Gene-Disease associations (from GenCC):

• White-Kernohan syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11671439).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015533.4. 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
	TKFC	NM_015533.4	MANE Select	c.364C>G	p.Arg122Gly	missense	Exon 5 of 18	NP_056348.2
	TKFC	NM_001351977.2		c.364C>G	p.Arg122Gly	missense	Exon 5 of 18	NP_001338906.1
	TKFC	NM_001351976.2		c.364C>G	p.Arg122Gly	missense	Exon 6 of 19	NP_001338905.1	Q3LXA3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TKFC	ENST00000394900.8	TSL:1 MANE Select	c.364C>G	p.Arg122Gly	missense	Exon 5 of 18	ENSP00000378360.3	Q3LXA3-1
	TKFC	ENST00000529479.5	TSL:1	c.361C>G	p.Arg121Gly	missense	Exon 3 of 16	ENSP00000432539.1	H0YCY6
	DDB1	ENST00000540166.5	TSL:2	n.-166+3055G>C		intron	N/A	ENSP00000440269.1	F5GY55

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461544 Hom.: 0 Cov.: 60 AF XY: 0.00 AC XY: 0 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.11	B
Vest4		0.48
MutPred		0.61		Loss of methylation at R122 (P = 0.0234)
MVP		0.13
MPC		0.25
ClinPred		0.40	T
GERP RS		1.1
Varity_R		0.23
gMVP		0.75
Mutation Taster		=93/7	polymorphism

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: rs149026556; hg19: chr11-61106785;