rs737054

Positions:

• chr6-35607710-G-A

Variant summary

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

The ENST00000357266.9(FKBP5):​c.509-10306C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 163,258 control chromosomes in the GnomAD database, including 4,644 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 0.22 (4211 hom., cov: 31)
  • Exomes 𝑓: 0.26 (433 hom.)
• Consequence: FKBP5 ENST00000357266.9 intron
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: 0.757

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]

RPL36P9 (HGNC:36746): (ribosomal protein L36 pseudogene 9)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 6-35607710-G-A is Pathogenic according to our data. Variant chr6-35607710-G-A is described in ClinVar as [Likely_risk_allele]. Clinvar id is 1702945.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=-0.6). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.509-10306C>T		intron_variant		ENST00000357266.9	NP_004108.1
FKBP5	NM_001145775.3	c.509-10306C>T		intron_variant			NP_001139247.1
FKBP5	NM_001145776.2	c.509-10306C>T		intron_variant			NP_001139248.1
FKBP5	NM_001145777.2	c.509-10306C>T		intron_variant			NP_001139249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.509-10306C>T		intron_variant		1	NM_004117.4	ENSP00000349811	P1
RPL36P9	ENST00000407266.1	n.83G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32717 AN: 151908 Hom.: 4202 Cov.: 31

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.265 AC: 2973 AN: 11232 Hom.: 433 Cov.: 0 AF XY: 0.265 AC XY: 1677 AN XY: 6338

Gnomad4 AFR exome AF: 0.0549

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.277

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.215 AC: 32734 AN: 152026 Hom.: 4211 Cov.: 31 AF XY: 0.214 AC XY: 15891 AN XY: 74286

Gnomad4 AFR AF: 0.0760

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.252

Alfa AF: 0.269 Hom.: 7810

Bravo AF: 0.216

Asia WGS AF: 0.240 AC: 833 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	-0.60
CADD	Benign	0.78
DANN	Benign	0.60

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: rs737054; hg19: chr6-35575487;