15-64156002-A-T

Position:

• chr15-64156002-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000942.5(PPIB):​c.*21T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,102 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (32 hom.)
• Consequence: PPIB NM_000942.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.179

Genes affected

PPIB (HGNC:9255): (peptidylprolyl isomerase B) The protein encoded by this gene is a cyclosporine-binding protein and is mainly located within the endoplasmic reticulum. It is associated with the secretory pathway and released in biological fluids. This protein can bind to cells derived from T- and B-lymphocytes, and may regulate cyclosporine A-mediated immunosuppression. Variants have been identified in this protein that give rise to recessive forms of osteogenesis imperfecta. [provided by RefSeq, Oct 2009]

SNX22 (HGNC:16315): (sorting nexin 22) The protein encoded by this gene is a sorting nexin that is found in the cytoplasm, where it interacts with membrane-bound phosphatidylinositol 3-phosphate. The encoded protein may play a role in intracellular trafficking. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Dec 2012]

SNX22 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-64156002-A-T is Benign according to our data. Variant chr15-64156002-A-T is described in ClinVar as [Benign]. Clinvar id is 886214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1812/152270) while in subpopulation AFR AF= 0.0419 (1741/41540). AF 95% confidence interval is 0.0403. There are 37 homozygotes in gnomad4. There are 840 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPIB	NM_000942.5	c.*21T>A		3_prime_UTR_variant	5/5	ENST00000300026.4	NP_000933.1
SNX22	NM_024798.3	c.*1494A>T		3_prime_UTR_variant	7/7	ENST00000325881.9	NP_079074.2
SNX22	XM_017022581.2	c.*1494A>T		3_prime_UTR_variant	6/6		XP_016878070.1
SNX22	NR_073534.2	n.2168A>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPIB	ENST00000300026	c.*21T>A		3_prime_UTR_variant	5/5	1	NM_000942.5	ENSP00000300026.4
SNX22	ENST00000325881.9	c.*1494A>T		3_prime_UTR_variant	7/7	1	NM_024798.3	ENSP00000323435.4

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1813 AN: 152152 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00311 AC: 776 AN: 249248 Hom.: 17 AF XY: 0.00212 AC XY: 286 AN XY: 134914

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00128 AC: 1869 AN: 1461832 Hom.: 32 Cov.: 30 AF XY: 0.00111 AC XY: 807 AN XY: 727214

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.0119 AC: 1812 AN: 152270 Hom.: 37 Cov.: 32 AF XY: 0.0113 AC XY: 840 AN XY: 74450

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00254 Hom.: 1

Bravo AF: 0.0137

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.78
CADD	Benign	3.3
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2307248; hg19: chr15-64448201;