rs137853883

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_021939.4(FKBP10):c.831delC(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 (★★). 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.727

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
FKBP10	NM_021939.4 link	c.831delC	p.Gly278AlafsTer20	frameshift_variant	Exon 5 of 10	ENST00000321562.9	NP_068758.3	Q96AY3-1A0A024R1W3Q8NAG5Q658U4
FKBP10	XM_011525099.4 link	c.831delC	p.Gly278AlafsTer20	frameshift_variant	Exon 5 of 11		XP_011523401.1
FKBP10	XM_011525100.3 link	c.558delC	p.Gly187AlafsTer20	frameshift_variant	Exon 4 of 10		XP_011523402.1
FKBP10	XM_047436515.1 link	c.558delC	p.Gly187AlafsTer20	frameshift_variant	Exon 4 of 9		XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9 link	c.831delC	p.Gly278AlafsTer20	frameshift_variant	Exon 5 of 10	1	NM_021939.4	ENSP00000317232.4		Q96AY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151468

Hom.:

Cov.:

show subpopulations

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:

AN:

250308

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135638

show subpopulations

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:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727140

show subpopulations

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:

AN:

151468

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73918

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 19, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Osteogenesis imperfecta type 11

Pathogenic:1

Jul 30, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Bruck syndrome 1;C3151218:Osteogenesis imperfecta type 11

Pathogenic:1

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over