chr17-41819452-G-T

Position:

• chr17-41819452-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_021939.4(FKBP10):​c.917+53G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,856 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (144 hom.)
• Consequence: FKBP10 NM_021939.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 0.0150

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00957 (1457/152250) while in subpopulation NFE AF= 0.0148 (1006/67992). AF 95% confidence interval is 0.014. There are 13 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP10	NM_021939.4	c.917+53G>T		intron_variant		ENST00000321562.9	NP_068758.3
FKBP10	XM_011525099.4	c.917+53G>T		intron_variant			XP_011523401.1
FKBP10	XM_011525100.3	c.644+53G>T		intron_variant			XP_011523402.1
FKBP10	XM_047436515.1	c.644+53G>T		intron_variant			XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9	c.917+53G>T		intron_variant		1	NM_021939.4	ENSP00000317232.4

Frequencies

GnomAD3 genomes AF: 0.00957 AC: 1456 AN: 152132 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.0125 AC: 18295 AN: 1461606 Hom.: 144 Cov.: 34 AF XY: 0.0129 AC XY: 9383 AN XY: 727106

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.0373

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00966

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.00957 AC: 1457 AN: 152250 Hom.: 13 Cov.: 32 AF XY: 0.00916 AC XY: 682 AN XY: 74450

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0134 Hom.: 2

Bravo AF: 0.00921

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	FKBP10: BS1, BS2 -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Osteogenesis imperfecta type 11 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_015860.1(NM_021939.3):c.917+53G>T in the FKBP10 gene has an allele frequency of 0.016 in European (non-Finnish) subpopulation in the gnomAD database, including four homozygous occurrences. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

FKBP10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs141387386; hg19: chr17-39975704;