rs3021522

Positions:

• chr12-2799979-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002014.4(FKBP4):​c.762+39C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,612,842 control chromosomes in the GnomAD database, including 3,273 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 0.065 (447 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2826 hom.)
• Consequence: FKBP4 NM_002014.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

Genes affected

FKBP4 (HGNC:3720): (FKBP prolyl isomerase 4) 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 has high structural and functional similarity to FK506-binding protein 1A (FKBP1A), but unlike FKBP1A, this protein does not have immunosuppressant activity when complexed with FK506. It interacts with interferon regulatory factor-4 and plays an important role in immunoregulatory gene expression in B and T lymphocytes. This encoded protein is known to associate with phytanoyl-CoA alpha-hydroxylase. It can also associate with two heat shock proteins (hsp90 and hsp70) and thus may play a role in the intracellular trafficking of hetero-oligomeric forms of the steroid hormone receptors. This protein correlates strongly with adeno-associated virus type 2 vectors (AAV) resulting in a significant increase in AAV-mediated transgene expression in human cell lines. Thus this encoded protein is thought to have important implications for the optimal use of AAV vectors in human gene therapy. The human genome contains several non-transcribed pseudogenes similar to this gene. [provided by RefSeq, Sep 2008]

(HGNC:):

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP4	NM_002014.4	c.762+39C>G		intron_variant		ENST00000001008.6
ITFG2-AS1	NR_146317.1	n.364-3033G>C		intron_variant, non_coding_transcript_variant
FKBP4	XM_047428539.1	c.627+39C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP4	ENST00000001008.6	c.762+39C>G		intron_variant		1	NM_002014.4	P1
	ENST00000547042.1	n.151-2707G>C		intron_variant, non_coding_transcript_variant		3
ITFG2-AS1	ENST00000547834.1	n.342-3033G>C		intron_variant, non_coding_transcript_variant		5
FKBP4	ENST00000543037.1	n.569+39C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9883 AN: 152126 Hom.: 448 Cov.: 33

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.0686

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0755

GnomAD3 exomes AF: 0.0687 AC: 17273 AN: 251398 Hom.: 925 AF XY: 0.0652 AC XY: 8864 AN XY: 135874

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0504 AC: 73655 AN: 1460598 Hom.: 2826 Cov.: 31 AF XY: 0.0503 AC XY: 36523 AN XY: 726696

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.0395

Gnomad4 EAS exome AF: 0.225

Gnomad4 SAS exome AF: 0.0614

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.0404

Gnomad4 OTH exome AF: 0.0625

GnomAD4 genome AF: 0.0651 AC: 9905 AN: 152244 Hom.: 447 Cov.: 33 AF XY: 0.0663 AC XY: 4935 AN XY: 74448

Gnomad4 AFR AF: 0.0750

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.0682

Gnomad4 FIN AF: 0.0361

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0517 Hom.: 44

Bravo AF: 0.0707

Asia WGS AF: 0.153 AC: 530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.47

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: rs3021522; hg19: chr12-2909145; COSMIC: COSV50008908; COSMIC: COSV50008908;