6-35575900-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS2

The NM_004117.4(FKBP5):c.1309G>T(p.Val437Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: FKBP5 NM_004117.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.799

Genes affected

FKBP5 (HGNC:3721): (FKBP prolyl isomerase 5) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

LOC101929309 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045993626).
• BP6: Variant 6-35575900-C-A is Benign according to our data. Variant chr6-35575900-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 736551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP5	NM_004117.4	c.1309G>T	p.Val437Phe	missense_variant	11/11	ENST00000357266.9
LOC101929309	XR_242006.4	n.182-17130C>A		intron_variant, non_coding_transcript_variant
FKBP5	NM_001145775.3	c.1309G>T	p.Val437Phe	missense_variant	12/12
FKBP5	NM_001145776.2	c.1309G>T	p.Val437Phe	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9	c.1309G>T	p.Val437Phe	missense_variant	11/11	1	NM_004117.4	P1
FKBP5	ENST00000536438.5	c.1309G>T	p.Val437Phe	missense_variant	12/12	1		P1
FKBP5	ENST00000539068.5	c.1309G>T	p.Val437Phe	missense_variant	11/11	1		P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000392 AC: 98 AN: 250176 Hom.: 2 AF XY: 0.000362 AC XY: 49 AN XY: 135318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00522

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461752 Hom.: 1 Cov.: 30 AF XY: 0.0000770 AC XY: 56 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00259

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000395 AC: 48

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	15
Dann	Benign	0.85
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.75	T;.;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.21		Loss of MoRF binding (P = 0.0867);Loss of MoRF binding (P = 0.0867);Loss of MoRF binding (P = 0.0867);
MVP		0.94
MPC		0.41
ClinPred		0.017	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.38

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: rs556530479; hg19: chr6-35543677;