9-113169892-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_015258.2(FKBP15):c.2817C>A(p.Ser939Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FKBP15 NM_015258.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

FKBP15 (HGNC:23397): (FKBP prolyl isomerase family member 15) Predicted to enable actin binding activity and peptidyl-prolyl cis-trans isomerase activity. Predicted to be involved in endocytosis and protein peptidyl-prolyl isomerization. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity FKB15_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10799748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP15	NM_015258.2	c.2817C>A	p.Ser939Arg	missense_variant	26/28	ENST00000238256.8
FKBP15	XM_006717018.3	c.2787C>A	p.Ser929Arg	missense_variant	26/28
FKBP15	XM_006717019.2	c.2613C>A	p.Ser871Arg	missense_variant	25/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP15	ENST00000238256.8	c.2817C>A	p.Ser939Arg	missense_variant	26/28	1	NM_015258.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397548 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 689272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 26, 2023

The c.2817C>A (p.S939R) alteration is located in exon 26 (coding exon 26) of the FKBP15 gene. This alteration results from a C to A substitution at nucleotide position 2817, causing the serine (S) at amino acid position 939 to be replaced by an arginine (R). 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	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.046
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.060
Sift	Benign	0.036	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.43	.;B
Vest4		0.29
MutPred		0.13		.;Loss of phosphorylation at S939 (P = 7e-04);
MVP		0.28
MPC		0.26
ClinPred		0.40	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095

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: rs1830175176; hg19: chr9-115932172;