chr17-41812852-C-G

Variant names:

• chr17-41812852-C-G
• rs533813401
• ENST00000429461.5:c.-93C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000429461.5(FKBP10):​c.-93C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 761,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: FKBP10 ENST00000429461.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.737
• 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]

P3H4 (HGNC:16946): (prolyl 3-hydroxylase family member 4 (inactive)) This nucleolar protein was first characterized because it was an autoantigen in cases on interstitial cystitis. The protein, with a predicted molecular weight of 50 kDa, appears to be localized in the particulate compartment of the interphase nucleolus, with a distribution distinct from that of nucleolar protein B23. During mitosis it is associated with chromosomes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000589 (359/609026) while in subpopulation NFE AF = 0.00082 (322/392778). AF 95% confidence interval is 0.000746. There are 1 homozygotes in GnomAdExome4. There are 151 alleles in the male GnomAdExome4 subpopulation. Median coverage is 8. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP10	NM_021939.4	c.-183C>G		upstream_gene_variant		ENST00000321562.9	NP_068758.3
FKBP10	XM_011525099.4	c.-183C>G		upstream_gene_variant			XP_011523401.1
FKBP10	XM_011525100.3	c.-310C>G		upstream_gene_variant			XP_011523402.1
FKBP10	XM_047436515.1	c.-310C>G		upstream_gene_variant			XP_047292471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP10	ENST00000321562.9	c.-183C>G		upstream_gene_variant		1	NM_021939.4	ENSP00000317232.4

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000589 AC: 359 AN: 609026 Hom.: 1 Cov.: 8 AF XY: 0.000476 AC XY: 151 AN XY: 317438

African (AFR) AF: 0.000118 AC: 2 AN: 16976

American (AMR) AF: 0.00 AC: 0 AN: 30924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16880

East Asian (EAS) AF: 0.00 AC: 0 AN: 31796

South Asian (SAS) AF: 0.00 AC: 0 AN: 54960

European-Finnish (FIN) AF: 0.000785 AC: 24 AN: 30592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2386

European-Non Finnish (NFE) AF: 0.000820 AC: 322 AN: 392778

Other (OTH) AF: 0.000347 AC: 11 AN: 31734

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74380

African (AFR) AF: 0.000120 AC: 5 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000336

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 11 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.16
PhyloP100		-0.74
PromoterAI		-0.30	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs533813401; hg19: chr17-39969104;