Variant NM_002014.4:c.979A>T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002014.4(FKBP4):c.979A>T(p.Met327Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FKBP4
NM_002014.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.88

Variant links:

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]

FKBP4 links:

ITFG2-AS1 (HGNC:):

ITFG2-AS1 links:

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

ITFG2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28548843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP4	NM_002014.4 link	c.979A>T	p.Met327Leu	missense_variant	Exon 8 of 10	ENST00000001008.6	NP_002005.1	Q02790
FKBP4	XM_047428539.1 link	c.844A>T	p.Met282Leu	missense_variant	Exon 8 of 10		XP_047284495.1
ITFG2-AS1	NR_146317.1 link	n.364-3578T>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FKBP4	ENST00000001008.6 link	c.979A>T	p.Met327Leu	missense_variant	Exon 8 of 10	1	NM_002014.4	ENSP00000001008.4	Q02790
ITFG2-AS1	ENST00000540093.2 link	n.342-3578T>A		intron_variant	Intron 1 of 3	3
ENSG00000258092	ENST00000547042.1 link	n.151-3252T>A		intron_variant	Intron 1 of 1	3
ITFG2-AS1	ENST00000547834.1 link	n.342-3578T>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.979A>T (p.M327L) alteration is located in exon 8 (coding exon 8) of the FKBP4 gene. This alteration results from a A to T substitution at nucleotide position 979, causing the methionine (M) at amino acid position 327 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.11

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0074

MetaRNN

Benign

0.29

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.47

REVEL

Benign

0.20

Sift

Benign

0.82

Sift4G

Benign

1.0

Polyphen

0.0080

Vest4

0.45

MutPred

0.69

Loss of MoRF binding (P = 0.1749);

MVP

0.75

MPC

0.55

ClinPred

0.79

GERP RS

4.3

Varity_R

0.27

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over