15-64162961-A-T

Variant names:

• chr15-64162961-A-T
• rs137853864
• NM_000942.5:c.26T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_000942.5(PPIB):​c.26T>A​(p.Met9Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M9V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPIB NM_000942.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.25
• Publications: 5 publications found

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]

PPIB Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-64162962-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3577595.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 15-64162961-A-T is Pathogenic according to our data. Variant chr15-64162961-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3339830.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000942.5. 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
	PPIB	NM_000942.5	MANE Select	c.26T>A	p.Met9Lys	missense	Exon 1 of 5	NP_000933.1	P23284

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIB	ENST00000300026.4	TSL:1 MANE Select	c.26T>A	p.Met9Lys	missense	Exon 1 of 5	ENSP00000300026.4	P23284
	PPIB	ENST00000561048.2	TSL:1	n.59T>A		non_coding_transcript_exon	Exon 1 of 4
	PPIB	ENST00000851557.1		c.26T>A	p.Met9Lys	missense	Exon 1 of 5	ENSP00000521616.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248020 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459000 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725876

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110406

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.034	D
Polyphen		0.97	D
Vest4		0.47
MutPred		0.71		Loss of stability (P = 0.0084)
MVP		0.92
MPC		0.62
ClinPred		0.87	D
GERP RS		5.2
PromoterAI		-0.23	Neutral
Varity_R		0.93
gMVP		0.87

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: rs137853864; hg19: chr15-64455160;