9-113169317-G-C

Position:

• chr9-113169317-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015258.2(FKBP15):​c.3392C>G​(p.Ser1131Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FKBP15 NM_015258.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0817413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP15	NM_015258.2	c.3392C>G	p.Ser1131Cys	missense_variant	26/28	ENST00000238256.8
FKBP15	XM_006717018.3	c.3362C>G	p.Ser1121Cys	missense_variant	26/28
FKBP15	XM_006717019.2	c.3188C>G	p.Ser1063Cys	missense_variant	25/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP15	ENST00000238256.8	c.3392C>G	p.Ser1131Cys	missense_variant	26/28	1	NM_015258.2	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000828

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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

Apr 18, 2023

The c.3392C>G (p.S1131C) alteration is located in exon 26 (coding exon 26) of the FKBP15 gene. This alteration results from a C to G substitution at nucleotide position 3392, causing the serine (S) at amino acid position 1131 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	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.97
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.046
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.68	.;P
Vest4		0.16
MVP		0.21
MPC		0.15
ClinPred		0.11	T
GERP RS		2.6
Varity_R		0.050

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: rs376981807; hg19: chr9-115931597;