rs114199361

Positions:

• chr17-41821650-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021939.4(FKBP10):​c.1400-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,764 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: FKBP10 NM_021939.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009654
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.05

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-41821650-C-G is Benign according to our data. Variant chr17-41821650-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 261437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41821650-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2210/152242) while in subpopulation AFR AF= 0.051 (2120/41552). AF 95% confidence interval is 0.0492. There are 51 homozygotes in gnomad4. There are 1055 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKBP10	NM_021939.4	c.1400-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000321562.9	NP_068758.3
FKBP10	XM_011525099.4	c.1457-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011523401.1
FKBP10	XM_011525100.3	c.1184-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011523402.1
FKBP10	XM_047436515.1	c.1127-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9	c.1400-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021939.4	ENSP00000317232	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2184 AN: 152124 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

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: 0.000132

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00357 AC: 897 AN: 250988 Hom.: 18 AF XY: 0.00273 AC XY: 370 AN XY: 135736

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1461522 Hom.: 35 Cov.: 34 AF XY: 0.00122 AC XY: 886 AN XY: 727078

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.0145 AC: 2210 AN: 152242 Hom.: 51 Cov.: 32 AF XY: 0.0142 AC XY: 1055 AN XY: 74432

Gnomad4 AFR AF: 0.0510

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00386 Hom.: 0

Bravo AF: 0.0164

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

Osteogenesis imperfecta type 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0020
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: rs114199361; hg19: chr17-39977902;