rs137853864

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-64162961-A-C
• chr15-64162961-A-T
• chr15-64162961-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000942.5(PPIB):​c.26T>G​(p.Met9Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). 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)
• Consequence: PPIB NM_000942.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O: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: Uncertain_significance. The variant received 4 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.

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>G	p.Met9Arg	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>G	p.Met9Arg	missense	Exon 1 of 5	ENSP00000300026.4	P23284
	PPIB	ENST00000561048.2	TSL:1	n.59T>G		non_coding_transcript_exon	Exon 1 of 4
	PPIB	ENST00000851557.1		c.26T>G	p.Met9Arg	missense	Exon 1 of 5	ENSP00000521616.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Osteogenesis imperfecta type 9 (2)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.052	T
Polyphen		0.97	D
Vest4		0.43
MutPred		0.74		Gain of methylation at K10 (P = 0.0276)
MVP		0.92
MPC		0.81
ClinPred		0.97	D
GERP RS		5.2
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.90
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;