1-39762513-T-C

Position:

• chr1-39762513-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000372830.5(PPIE):​c.838-4T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,549,386 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (65 hom.)
• Consequence: PPIE ENST00000372830.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008058
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310

Genes affected

BMP8B (HGNC:1075): (bone morphogenetic protein 8b) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The encoded protein stimulates thermogenesis in brown adipose tissue. Expression of this gene may be downregulated in pancreatic cancer. This gene may have arose from a gene duplication event and its gene duplicate is also present on chromosome 1. [provided by RefSeq, Jul 2016]

PPIE (HGNC:9258): (peptidylprolyl isomerase E) The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein contains a highly conserved cyclophilin (CYP) domain as well as an RNA-binding domain. It was shown to possess PPIase and protein folding activities, and it also exhibits RNA-binding activity. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 1, has been identified. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-39762513-T-C is Benign according to our data. Variant chr1-39762513-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 773107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1002 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP8B	NM_001720.5	c.1059+579A>G		intron_variant		ENST00000372827.8	NP_001711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP8B	ENST00000372827.8	c.1059+579A>G		intron_variant		1	NM_001720.5	ENSP00000361915	P1
PPIE	ENST00000356511.6	c.838-1176T>C		intron_variant		1		ENSP00000348904
PPIE	ENST00000372830.5	c.838-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000361918
PPIE	ENST00000467741.2	n.266-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1002 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00640 AC: 946 AN: 147886 Hom.: 9 AF XY: 0.00612 AC XY: 488 AN XY: 79682

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.0000931

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00735 AC: 10273 AN: 1397094 Hom.: 65 Cov.: 31 AF XY: 0.00713 AC XY: 4916 AN XY: 689110

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00702

Gnomad4 ASJ exome AF: 0.000637

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00802

Gnomad4 OTH exome AF: 0.00685

GnomAD4 genome AF: 0.00658 AC: 1002 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00704 AC XY: 524 AN XY: 74476

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.00847

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00689 Hom.: 1

Bravo AF: 0.00570

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	BMP8B: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.57
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0020
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: rs192079535; hg19: chr1-40228185;