NM_021939.4:c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC

Variant names:

• chr17-41813025-TCCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGC-T
• NM_021939.4:c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_021939.4(FKBP10):​c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP10 NM_021939.4 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.85
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Illumina
• 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
• PP5: Variant 17-41813025-TCCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGC-T is Pathogenic according to our data. Variant chr17-41813025-TCCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 871073.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP10	NM_021939.4	c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 10	ENST00000321562.9	NP_068758.3
FKBP10	NM_021939.4	c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC		5_prime_UTR_variant	Exon 1 of 10	ENST00000321562.9	NP_068758.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9	c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 10	1	NM_021939.4	ENSP00000317232.4
FKBP10	ENST00000321562.9	c.-8_78delCAGGCACCATGTTCCCCGCGGGCCCCCCCAGCCACAGCCTCCTCCGGCTCCCCCTGCTGCAGTTGCTGCTACTGGTGGTGCAGGCC		5_prime_UTR_variant	Exon 1 of 10	1	NM_021939.4	ENSP00000317232.4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=17/183	disease causing (ClinVar)

Splicing

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

Other links and lift over

hg19: chr17-39969277;