chr12-2798560-A-T

Variant names:

• chr12-2798560-A-T
• rs1981655
• NM_002014.4:c.394-146A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 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.394-146A>T		intron	N/A	NP_002005.1
	ITFG2-AS1	NR_146317.1		n.364-1614T>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP4	ENST00000001008.6	TSL:1 MANE Select	c.394-146A>T		intron	N/A	ENSP00000001008.4
	ITFG2-AS1	ENST00000540093.2	TSL:3	n.342-1614T>A		intron	N/A
	ITFG2-AS1	ENST00000545526.2	TSL:2	n.547-1614T>A		intron	N/A

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

African (AFR) AF: 0.0772 AC: 2069 AN: 26786

American (AMR) AF: 0.115 AC: 3773 AN: 32830

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 761 AN: 19286

East Asian (EAS) AF: 0.216 AC: 7953 AN: 36860

South Asian (SAS) AF: 0.0614 AC: 4261 AN: 69402

European-Finnish (FIN) AF: 0.0357 AC: 1550 AN: 43414

Middle Eastern (MID) AF: 0.0414 AC: 137 AN: 3306

European-Non Finnish (NFE) AF: 0.0395 AC: 34897 AN: 884474

Other (OTH) AF: 0.0612 AC: 3029 AN: 49498

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

African (AFR) AF: 0.0778 AC: 3233 AN: 41538

American (AMR) AF: 0.110 AC: 1685 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1038 AN: 5160

South Asian (SAS) AF: 0.0687 AC: 331 AN: 4816

European-Finnish (FIN) AF: 0.0363 AC: 385 AN: 10610

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0432 AC: 2941 AN: 68018

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.68
PhyloP100		1.0
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: rs1981655; hg19: chr12-2907726; COSMIC: COSV50009653; COSMIC: COSV50009653;