rs141387386

Variant names:

• chr17-41819452-G-T
• rs141387386
• NM_021939.4:c.917+53G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41819452-G-T
• chr17-41819452-G-A

Variant summary

Our verdict is Benign. The variant received -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:2 B:3
• Conservation: PhyloP100: 0.0150
• Publications: 0 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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.917+53G>T		intron	N/A	NP_068758.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP10	ENST00000321562.9	TSL:1 MANE Select	c.917+53G>T		intron	N/A	ENSP00000317232.4	Q96AY3-1
	FKBP10	ENST00000914601.1		c.917+53G>T		intron	N/A	ENSP00000584660.1
	FKBP10	ENST00000864398.1		c.917+53G>T		intron	N/A	ENSP00000534457.1

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

African (AFR) AF: 0.00149 AC: 50 AN: 33478

American (AMR) AF: 0.00474 AC: 212 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0373 AC: 974 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0158 AC: 1360 AN: 86242

European-Finnish (FIN) AF: 0.00966 AC: 515 AN: 53286

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5768

European-Non Finnish (NFE) AF: 0.0127 AC: 14092 AN: 1111902

Other (OTH) AF: 0.0146 AC: 884 AN: 60388

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

African (AFR) AF: 0.00180 AC: 75 AN: 41554

American (AMR) AF: 0.00412 AC: 63 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4824

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1006 AN: 67992

Other (OTH) AF: 0.0119 AC: 25 AN: 2106

Alfa AF: 0.0148 Hom.: 19

Bravo AF: 0.00921

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Osteogenesis imperfecta type 11 (3)
1	-	1	not provided (2)
-	-	1	FKBP10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.53
PhyloP100		0.015
PromoterAI		-0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141387386; hg19: chr17-39975704;