17-82722876-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024619.4(FN3KRP):c.458A>G(p.Tyr153Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000033 in 151,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000033 (0 hom., cov: 33)
• Consequence: FN3KRP NM_024619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

FN3KRP (HGNC:25700): (fructosamine 3 kinase related protein) A high concentration of glucose can result in non-enzymatic oxidation of proteins by reaction of glucose and lysine residues (glycation). Proteins modified in this way are less active or functional. This gene encodes an enzyme which catalyzes the phosphorylation of psicosamines and ribulosamines compared to the neighboring gene which encodes a highly similar enzyme, fructosamine-3-kinase, which has different substrate specificity. The activity of both enzymes may result in deglycation of proteins to restore their function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FN3KRP	NM_024619.4	c.458A>G	p.Tyr153Cys	missense_variant	4/6	ENST00000269373.11
FN3KRP	NR_046408.2	n.636A>G		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FN3KRP	ENST00000269373.11	c.458A>G	p.Tyr153Cys	missense_variant	4/6	1	NM_024619.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151614 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000971

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151614 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73984

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.458A>G (p.Y153C) alteration is located in exon 4 (coding exon 4) of the FN3KRP gene. This alteration results from a A to G substitution at nucleotide position 458, causing the tyrosine (Y) at amino acid position 153 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.051	T;D
Polyphen		1.0	D;.
Vest4		0.89
MVP		0.62
MPC		0.50
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.78

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: rs893353540; hg19: chr17-80680752;