12-2803151-G-T

Position:

• chr12-2803151-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002014.4(FKBP4):​c.1273G>T​(p.Ala425Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKBP4 NM_002014.4 missense, splice_region
• Scores: Splicing: ADA: 0.3083
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.972

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.099750906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP4	NM_002014.4	c.1273G>T	p.Ala425Ser	missense_variant, splice_region_variant	10/10	ENST00000001008.6	NP_002005.1
ITFG2-AS1	NR_146317.1	n.364-6205C>A		intron_variant, non_coding_transcript_variant
FKBP4	XM_047428539.1	c.1138G>T	p.Ala380Ser	missense_variant, splice_region_variant	10/10		XP_047284495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP4	ENST00000001008.6	c.1273G>T	p.Ala425Ser	missense_variant, splice_region_variant	10/10	1	NM_002014.4	ENSP00000001008	P1
	ENST00000547042.1	n.150+638C>A		intron_variant, non_coding_transcript_variant		3
ITFG2-AS1	ENST00000547834.1	n.342-6205C>A		intron_variant, non_coding_transcript_variant		5
FKBP4	ENST00000544366.1			upstream_gene_variant		3		ENSP00000442193

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000988

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446526 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 718344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 08, 2023

The c.1273G>T (p.A425S) alteration is located in exon 10 (coding exon 10) of the FKBP4 gene. This alteration results from a G to T substitution at nucleotide position 1273, causing the alanine (A) at amino acid position 425 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.75
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.18
Sift	Benign	0.52	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.56
MPC		0.31
ClinPred		0.037	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -31

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

Publications

LitVar

Other links and lift over

dbSNP: rs773339152; hg19: chr12-2912317;