12-2798560-A-T

Position:

• chr12-2798560-A-T

Variant summary

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

The NM_002014.4(FKBP4):​c.394-146A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,318,084 control chromosomes in the GnomAD database, including 2,750 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 0.066 (450 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2300 hom.)
• Consequence: FKBP4 NM_002014.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP4	NM_002014.4	c.394-146A>T		intron_variant		ENST00000001008.6	NP_002005.1
ITFG2-AS1	NR_146317.1	n.364-1614T>A		intron_variant, non_coding_transcript_variant
FKBP4	XM_047428539.1	c.259-146A>T		intron_variant			XP_047284495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP4	ENST00000001008.6	c.394-146A>T		intron_variant		1	NM_002014.4	ENSP00000001008	P1
	ENST00000547042.1	n.151-1288T>A		intron_variant, non_coding_transcript_variant		3
ITFG2-AS1	ENST00000547834.1	n.342-1614T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9946 AN: 152110 Hom.: 450 Cov.: 33

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0755

GnomAD4 exome AF: 0.0501 AC: 58430 AN: 1165856 Hom.: 2300 AF XY: 0.0499 AC XY: 29007 AN XY: 580794

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.0395

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.0614

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0655 AC: 9971 AN: 152228 Hom.: 450 Cov.: 33 AF XY: 0.0666 AC XY: 4957 AN XY: 74444

Gnomad4 AFR AF: 0.0778

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.0687

Gnomad4 FIN AF: 0.0363

Gnomad4 NFE AF: 0.0432

Gnomad4 OTH AF: 0.0776

Alfa AF: 0.0552 Hom.: 36

Bravo AF: 0.0712

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.68

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: rs1981655; hg19: chr12-2907726; COSMIC: COSV50009653; COSMIC: COSV50009653;