rs3021522

Variant names:

• chr12-2799979-C-G
• rs3021522
• NM_002014.4:c.762+39C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002014.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP4	NM_002014.4	MANE Select	c.762+39C>G		intron	N/A	NP_002005.1
	ITFG2-AS1	NR_146317.1		n.364-3033G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP4	ENST00000001008.6	TSL:1 MANE Select	c.762+39C>G		intron	N/A	ENSP00000001008.4
	ITFG2-AS1	ENST00000540093.2	TSL:3	n.342-3033G>C		intron	N/A
	FKBP4	ENST00000543037.1	TSL:2	n.569+39C>G		intron	N/A

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

GnomAD2 exomes AF: 0.0687 AC: 17273 AN: 251398 AF XY: 0.0652

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 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

African (AFR) AF: 0.0738 AC: 2470 AN: 33448

American (AMR) AF: 0.114 AC: 5104 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 1033 AN: 26132

East Asian (EAS) AF: 0.225 AC: 8934 AN: 39694

South Asian (SAS) AF: 0.0614 AC: 5299 AN: 86240

European-Finnish (FIN) AF: 0.0360 AC: 1924 AN: 53420

Middle Eastern (MID) AF: 0.0413 AC: 238 AN: 5768

European-Non Finnish (NFE) AF: 0.0404 AC: 44879 AN: 1110840

Other (OTH) AF: 0.0625 AC: 3774 AN: 60336

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

African (AFR) AF: 0.0750 AC: 3116 AN: 41532

American (AMR) AF: 0.109 AC: 1672 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3472

East Asian (EAS) AF: 0.211 AC: 1091 AN: 5168

South Asian (SAS) AF: 0.0682 AC: 329 AN: 4822

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0435 AC: 2956 AN: 68024

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.47
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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