rs869320752

Variant names:

• chr17-41819356-CACT-C
• rs869320752
• NM_021939.4:c.877_879delTAC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_021939.4(FKBP10):​c.877_879delTAC​(p.Tyr293del) variant causes a conservative 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 (★★). ClinVar reports functional evidence for this variant: "SCV004813218: 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). PMID:23712425". Synonymous variant affecting the same amino acid position (i.e. Y293Y) has been classified as Likely benign.

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

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]

FKBP10 Gene-Disease associations (from GenCC):

• Bruck syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• osteogenesis imperfecta type 11

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis-like syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Bruck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004813218: 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). PMID: 23712425
• 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 VariationId is 208427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP10	NM_021939.4	MANE Select	c.877_879delTAC	p.Tyr293del	conservative_inframe_deletion	Exon 5 of 10	NP_068758.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP10	ENST00000321562.9	TSL:1 MANE Select	c.877_879delTAC	p.Tyr293del	conservative_inframe_deletion	Exon 5 of 10	ENSP00000317232.4	Q96AY3-1
	FKBP10	ENST00000914601.1		c.877_879delTAC	p.Tyr293del	conservative_inframe_deletion	Exon 5 of 11	ENSP00000584660.1
	FKBP10	ENST00000864398.1		c.877_879delTAC	p.Tyr293del	conservative_inframe_deletion	Exon 5 of 12	ENSP00000534457.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bruck syndrome 1 (1)
1	-	-	not provided (1)
1	-	-	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs869320752; hg19: chr17-39975608;