12-2801350-G-C

Position:

• chr12-2801350-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002014.4(FKBP4):​c.1266G>C​(p.Glu422Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP4 NM_002014.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.499

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03547442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP4	NM_002014.4	c.1266G>C	p.Glu422Asp	missense_variant	9/10	ENST00000001008.6	NP_002005.1
ITFG2-AS1	NR_146317.1	n.364-4404C>G		intron_variant, non_coding_transcript_variant
FKBP4	XM_047428539.1	c.1131G>C	p.Glu377Asp	missense_variant	9/10		XP_047284495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP4	ENST00000001008.6	c.1266G>C	p.Glu422Asp	missense_variant	9/10	1	NM_002014.4	ENSP00000001008	P1
	ENST00000547042.1	n.150+2439C>G		intron_variant, non_coding_transcript_variant		3
ITFG2-AS1	ENST00000547834.1	n.342-4404C>G		intron_variant, non_coding_transcript_variant		5
FKBP4	ENST00000539181.1	c.174G>C	p.Glu58Asp	missense_variant	1/2	3		ENSP00000438491

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248068 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.1266G>C (p.E422D) alteration is located in exon 9 (coding exon 9) of the FKBP4 gene. This alteration results from a G to C substitution at nucleotide position 1266, causing the glutamic acid (E) at amino acid position 422 to be replaced by an aspartic acid (D). 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	0.081
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.1
DANN	Benign	0.76
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.065	N
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.25		Loss of helix (P = 0.0093);
MVP		0.62
MPC		0.31
ClinPred		0.021	T
GERP RS		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.087

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: rs1033322201; hg19: chr12-2910516;