15-64155943-G-A

Position:

• chr15-64155943-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000942.5(PPIB):​c.*80C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,606,420 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: PPIB NM_000942.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.29

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000328 (50/152258) while in subpopulation SAS AF= 0.00269 (13/4828). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPIB	NM_000942.5	c.*80C>T		3_prime_UTR_variant	5/5	ENST00000300026.4	NP_000933.1
SNX22	NM_024798.3	c.*1435G>A		3_prime_UTR_variant	7/7	ENST00000325881.9	NP_079074.2
SNX22	XM_017022581.2	c.*1435G>A		3_prime_UTR_variant	6/6		XP_016878070.1
SNX22	NR_073534.2	n.2109G>A		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPIB	ENST00000300026	c.*80C>T		3_prime_UTR_variant	5/5	1	NM_000942.5	ENSP00000300026.4
SNX22	ENST00000325881.9	c.*1435G>A		3_prime_UTR_variant	7/7	1	NM_024798.3	ENSP00000323435.4

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 279 AN: 1454162 Hom.: 3 Cov.: 29 AF XY: 0.000267 AC XY: 193 AN XY: 723758

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74440

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000283

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 9 Uncertain:1

Uncertain significance, 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, 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	-0.79
CADD	Benign	0.12
DANN	Benign	0.73
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: rs540855873; hg19: chr15-64448142;