17-41813055-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_021939.4(FKBP10):c.21C>T(p.Pro7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,610,298 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (4 hom.)
• Consequence: FKBP10 NM_021939.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.67

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-41813055-C-T is Benign according to our data. Variant chr17-41813055-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286621.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=1}.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000193 (282/1457988) while in subpopulation MID AF= 0.00846 (36/4256). AF 95% confidence interval is 0.00628. There are 4 homozygotes in gnomad4_exome. There are 156 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKBP10	NM_021939.4	c.21C>T	p.Pro7=	synonymous_variant	1/10	ENST00000321562.9
FKBP10	XM_011525099.4	c.21C>T	p.Pro7=	synonymous_variant	1/11
FKBP10	XM_011525100.3	c.-107C>T		5_prime_UTR_variant	1/10
FKBP10	XM_047436515.1	c.-107C>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKBP10	ENST00000321562.9	c.21C>T	p.Pro7=	synonymous_variant	1/10	1	NM_021939.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000293 AC: 70 AN: 239160 Hom.: 0 AF XY: 0.000296 AC XY: 39 AN XY: 131646

Gnomad AFR exome AF: 0.000143

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000193 AC: 282 AN: 1457988 Hom.: 4 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 725266

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74476

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000162

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FKBP10: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Osteogenesis imperfecta type 11 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	12
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs781985978; hg19: chr17-39969307; COSMIC: COSV58638689; COSMIC: COSV58638689;