6-35584850-A-G

Position:

• chr6-35584850-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001145777.2(FKBP5):​c.*2126T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 985,368 control chromosomes in the GnomAD database, including 414 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.035 (127 hom., cov: 32)
  • Exomes 𝑓: 0.023 (287 hom.)
• Consequence: FKBP5 NM_001145777.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP5	NM_004117.4	c.840+2184T>C		intron_variant		ENST00000357266.9	NP_004108.1
FKBP5	NM_001145777.2	c.*2126T>C		3_prime_UTR_variant	7/7		NP_001139249.1
FKBP5	NM_001145775.3	c.840+2184T>C		intron_variant			NP_001139247.1
FKBP5	NM_001145776.2	c.840+2184T>C		intron_variant			NP_001139248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP5	ENST00000357266.9	c.840+2184T>C		intron_variant		1	NM_004117.4	ENSP00000349811.3
FKBP5	ENST00000536438.5	c.840+2184T>C		intron_variant		1		ENSP00000444810.1
FKBP5	ENST00000539068.5	c.840+2184T>C		intron_variant		1		ENSP00000441205.1
FKBP5	ENST00000542713	c.*2126T>C		3_prime_UTR_variant	7/7	2		ENSP00000442340.1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5396 AN: 152160 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0363

GnomAD4 exome AF: 0.0234 AC: 19502 AN: 833090 Hom.: 287 Cov.: 31 AF XY: 0.0233 AC XY: 8969 AN XY: 384706

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.0571

Gnomad4 EAS exome AF: 0.00138

Gnomad4 SAS exome AF: 0.00383

Gnomad4 FIN exome AF: 0.00725

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0355 AC: 5399 AN: 152278 Hom.: 127 Cov.: 32 AF XY: 0.0342 AC XY: 2550 AN XY: 74474

Gnomad4 AFR AF: 0.0694

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0263 Hom.: 67

Bravo AF: 0.0377

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.85

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: rs16878591; hg19: chr6-35552627;