rs137853883

chr17-41819306-TC-Tchr17-41819306-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_021939.4(FKBP10):c.831del(p.Gly278AlafsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L275L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FKBP10 NM_021939.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.727

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-41819306-TC-T is Pathogenic according to our data. Variant chr17-41819306-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 503914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41819306-TC-T is described in Lovd as [Pathogenic]. Variant chr17-41819306-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP10	NM_021939.4	c.831del	p.Gly278AlafsTer20	frameshift_variant	5/10	ENST00000321562.9
FKBP10	XM_011525099.4	c.831del	p.Gly278AlafsTer20	frameshift_variant	5/11
FKBP10	XM_011525100.3	c.558del	p.Gly187AlafsTer20	frameshift_variant	4/10
FKBP10	XM_047436515.1	c.558del	p.Gly187AlafsTer20	frameshift_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP10	ENST00000321562.9	c.831del	p.Gly278AlafsTer20	frameshift_variant	5/10	1	NM_021939.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151468 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250308 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135638

Gnomad AFR exome AF: 0.0000623

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151468 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73918

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2017	The c.831delC variant in the FKBP10 gene has been previously reported in multiple individuals with osteogenesis imperfecta type 3 who carry a second FKBP10 pathogenic variant (Vorster et al., 2017). This deletion causes a frameshift starting with codon Glycine 278, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Gly278AlafsX20. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.831delC to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change creates a premature translational stop signal (p.Gly278Alafs*20) in the FKBP10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP10 are known to be pathogenic (PMID: 22689593, 22949511). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta (PMID: 28492130). ClinVar contains an entry for this variant (Variation ID: 503914). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta type 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 30, 2019

The FKBP10 c.831delC (p.Gly278AlafsTer20) variant results in a frameshift and is predicted to result in a premature truncation of the protein. The p.Gly278AlafsTer20 variant has been reported in a compound heterozygous state in eight individuals with osteogenesis imperfecta, including in three siblings and in at least three different families, and in a heterozygous state in one healthy parent of an affected individual (Vorster et al. 2017; Zhang et al. 2018; Chetty et al. 2019). In the seven individuals reported by Voster et al. (2017) and Chetty et al. (2019), all of whom were from southern Africa, the p.Gly278AlafsTer20 variant was identified in trans with another frameshift variant that occurs at the same nucleotide position, c.831dupC (p.Gly278ArgfsTer95), a pathogenic variant that Voster et al. (2017) suggest to be a founder variant in black southern African populations. In the remaining case, a male of Chinese heritage, the p.Gly278AlafsTer20 variant was found in trans with a different frameshift variant (Zhang et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000081 in the African population of the Genome Aggregation Database. Chetty et al. (2019) indicate that the p.Gly278AlafsTer20 variant results in the loss of two peptidylprolyl isomerase domains and two EF-hand domains, which are important for appropriate protein localization. Based on the available evidence, the c.831delC (p.Gly278AlafsTer20) variant is classified as pathogenic for osteogenesis imperfecta with or without joint contractures. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137853883; hg19: chr17-39975558;