rs114199361

Variant names:

• chr17-41821650-C-G
• rs114199361
• NM_021939.4:c.1400-4C>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00009654
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.05
• Publications: 1 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 -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 Benign/Likely_benign. ClinVar VariationId is 261437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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.1400-4C>G		splice_region 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.1400-4C>G		splice_region intron	N/A	ENSP00000317232.4	Q96AY3-1
	FKBP10	ENST00000914601.1		c.1721-4C>G		splice_region intron	N/A	ENSP00000584660.1
	FKBP10	ENST00000864398.1		c.1640-4C>G		splice_region intron	N/A	ENSP00000534457.1

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

GnomAD2 exomes AF: 0.00357 AC: 897 AN: 250988 AF XY: 0.00273

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 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

African (AFR) AF: 0.0509 AC: 1702 AN: 33464

American (AMR) AF: 0.00244 AC: 109 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000904 AC: 5 AN: 5534

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111978

Other (OTH) AF: 0.00278 AC: 168 AN: 60350

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

African (AFR) AF: 0.0510 AC: 2120 AN: 41552

American (AMR) AF: 0.00412 AC: 63 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68006

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteogenesis imperfecta type 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114199361; hg19: chr17-39977902;