chr17-41819306-T-TC

Variant names:

• chr17-41819306-T-TC
• rs137853883
• NM_021939.4:c.831dupC

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_021939.4(FKBP10):​c.831dupC​(p.Gly278ArgfsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004801520: In studies on mRNA isolated from patient cells, the p.Gly278ArgfsTer95 was shown to affect mRNA stability resulting in no measurable stable mRNA and absence of protein on Western blotting (Schwarze et al. 2013).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: FKBP10 NM_021939.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1
• Conservation: PhyloP100: -0.727
• Publications: 29 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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004801520: In studies on mRNA isolated from patient cells, the p.Gly278ArgfsTer95 was shown to affect mRNA stability resulting in no measurable stable mRNA and absence of protein on Western blotting (Schwarze et al. 2013).
• PP5: Variant 17-41819306-T-TC is Pathogenic according to our data. Variant chr17-41819306-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 438659.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.831dupC	p.Gly278ArgfsTer95	frameshift	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.831dupC	p.Gly278ArgfsTer95	frameshift	Exon 5 of 10	ENSP00000317232.4	Q96AY3-1
	FKBP10	ENST00000914601.1		c.831dupC	p.Gly278ArgfsTer78	frameshift	Exon 5 of 11	ENSP00000584660.1
	FKBP10	ENST00000864398.1		c.831dupC	p.Gly278ArgfsTer78	frameshift	Exon 5 of 12	ENSP00000534457.1

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151466 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 250308 AF XY: 0.0000811

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.0000921 AC XY: 67 AN XY: 727122

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111946

Other (OTH) AF: 0.000149 AC: 9 AN: 60388

GnomAD4 genome AF: 0.000152 AC: 23 AN: 151580 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 9 AN XY: 74042

African (AFR) AF: 0.000363 AC: 15 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.0000952 AC: 1 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67912

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	1	-	Osteogenesis imperfecta type 11 (10)
6	-	-	not provided (6)
1	-	-	Abnormality of the skeletal system (1)
1	-	-	Bruck syndrome 1 (1)
1	-	-	Bruck syndrome 1;C3151218:Osteogenesis imperfecta type 11 (1)
1	-	-	Osteogenesis imperfecta (1)
1	-	-	Osteogenesis imperfecta type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.73
Mutation Taster		=16/184	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137853883; hg19: chr17-39975558; COSMIC: COSV58636802; COSMIC: COSV58636802;