6-35611598-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_004117.4(FKBP5):c.508+7498T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,140 control chromosomes in the GnomAD database, including 51,699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: 𝑓 0.82 (51699 hom., cov: 31)
• Consequence: FKBP5 NM_004117.4 intron
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: -4.46

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 6-35611598-A-C is Pathogenic according to our data. Variant chr6-35611598-A-C is described in ClinVar as [Likely_risk_allele]. Clinvar id is 1702942.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).. Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP5	NM_004117.4	c.508+7498T>G		intron_variant		ENST00000357266.9
FKBP5	NM_001145775.3	c.508+7498T>G		intron_variant
FKBP5	NM_001145776.2	c.508+7498T>G		intron_variant
FKBP5	NM_001145777.2	c.508+7498T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP5	ENST00000357266.9	c.508+7498T>G		intron_variant		1	NM_004117.4	P1
FKBP5	ENST00000536438.5	c.508+7498T>G		intron_variant		1		P1
FKBP5	ENST00000539068.5	c.508+7498T>G		intron_variant		1		P1
FKBP5	ENST00000542713.1	c.508+7498T>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.823 AC: 125153 AN: 152022 Hom.: 51646 Cov.: 31

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.793

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.823 AC: 125263 AN: 152140 Hom.: 51699 Cov.: 31 AF XY: 0.824 AC XY: 61289 AN XY: 74394

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.784

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.859

Gnomad4 NFE AF: 0.817

Gnomad4 OTH AF: 0.787

Alfa AF: 0.814 Hom.: 79650

Bravo AF: 0.823

Asia WGS AF: 0.754 AC: 2621 AN: 3478

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Susceptibility to severe depressive disorder Pathogenic:1

Likely risk allele, no assertion criteria provided

case-control

Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology

Jul 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.0080
Dann	Benign	0.49

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: rs6926133; hg19: chr6-35579375;