chr1-39522412-G-A

Position:

• chr1-39522412-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181809.4(BMP8A):​c.878G>A​(p.Arg293His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 136,950 control chromosomes in the GnomAD database, including 13,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.44 (13820 hom., cov: 28)
  • Exomes 𝑓: 0.51 (174929 hom.)
  • Failed GnomAD Quality Control
• Consequence: BMP8A NM_181809.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0210

Genes affected

BMP8A (HGNC:21650): (bone morphogenetic protein 8a) 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. This protein may play a role in development of the reproductive system. 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]

PPIEL (HGNC:33195): (peptidylprolyl isomerase E like (pseudogene)) This transcribed pseudogene is related to PPIE (Gene ID: 10450). Expression of this pseudogene may be downregulated in non-small cell lung cancer (NSCLC). Differential DNA methylation of this locus may be associated with intellectual disability and bipolar disorder in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004436791).
• BP6: Variant 1-39522412-G-A is Benign according to our data. Variant chr1-39522412-G-A is described in ClinVar as [Benign]. Clinvar id is 767666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP8A	NM_181809.4	c.878G>A	p.Arg293His	missense_variant	5/7	ENST00000331593.6	NP_861525.2
PPIEL	NR_003929.2	n.2505C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP8A	ENST00000331593.6	c.878G>A	p.Arg293His	missense_variant	5/7	1	NM_181809.4	ENSP00000327440	P1
PPIEL	ENST00000692918.1	n.1151C>T		non_coding_transcript_exon_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.445 AC: 60877 AN: 136834 Hom.: 13814 Cov.: 28

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.447

GnomAD3 exomes AF: 0.469 AC: 83984 AN: 179010 Hom.: 25205 AF XY: 0.486 AC XY: 46889 AN XY: 96516

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.691

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.514 AC: 598076 AN: 1163002 Hom.: 174929 Cov.: 43 AF XY: 0.521 AC XY: 302485 AN XY: 580912

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.467

Gnomad4 NFE exome AF: 0.511

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.445 AC: 60892 AN: 136950 Hom.: 13820 Cov.: 28 AF XY: 0.449 AC XY: 29845 AN XY: 66404

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.516

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.446

Alfa AF: 0.400 Hom.: 1571

ExAC AF: 0.463 AC: 56239

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.1
DANN	Benign	0.68
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.088	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.088
Sift	Benign	0.83	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.091
MPC		1.8
ClinPred		0.00071	T
GERP RS		3.3
Varity_R		0.021
gMVP		0.28

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: rs6525; hg19: chr1-39988084; COSMIC: COSV59032023; COSMIC: COSV59032023;