rs869320752

chr17-41819356-CACT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_021939.4(FKBP10):c.877_879del(p.Tyr293del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FKBP10 NM_021939.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.60

Genes affected

FKBP10 (HGNC:18169): (FKBP prolyl isomerase 10) The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. This protein localizes to the endoplasmic reticulum and acts as a molecular chaperone. Alternatively spliced variants encoding different isoforms have been reported, but their biological validity has not been determined.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021939.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-41819356-CACT-C is Pathogenic according to our data. Variant chr17-41819356-CACT-C is described in ClinVar as [Pathogenic]. Clinvar id is 208427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP10	NM_021939.4	c.877_879del	p.Tyr293del	inframe_deletion	5/10	ENST00000321562.9
FKBP10	XM_011525099.4	c.877_879del	p.Tyr293del	inframe_deletion	5/11
FKBP10	XM_011525100.3	c.604_606del	p.Tyr202del	inframe_deletion	4/10
FKBP10	XM_047436515.1	c.604_606del	p.Tyr202del	inframe_deletion	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP10	ENST00000321562.9	c.877_879del	p.Tyr293del	inframe_deletion	5/10	1	NM_021939.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 23, 2024

Variant summary: FKBP10 c.877_879delTAC (p.Tyr293del) results in an in-frame deletion that is predicted to remove one amino acid in the FKBP-type peptidyl-prolyl cis-trans isomerase domain (IPR001179) from the encoded protein. The variant was absent in 251136 control chromosomes. c.877_879delTAC has been reported at a homozygous state in the literature in multiple individuals affected with Kuskokwim syndrome. These data indicate that the variant is very likely to be associated with disease (Barnes_2013). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a residual 5% of normal FKBP65 protein levels due to destability and compromised hydroxylation levels of the telopeptide lysine in fibroblasts from patients with the homozygous variant (Barnes_2013). The following publication has been ascertained in the context of this evaluation (PMID: 23712425).ClinVar contains an entry for this variant (Variation ID: 208427). Based on the evidence outlined above, the variant was classified as pathogenic. -

Bruck syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2022

In-frame deletion of 1 amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23712425, 34173012) -

Computational scores

Source: dbNSFP v4.3

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: rs869320752; hg19: chr17-39975608;