chr6-55766964-G-A

Variant names:

• chr6-55766964-G-A
• rs228144
• NM_021073.4:c.1028-6431C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021073.4(BMP5):​c.1028-6431C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 152,032 control chromosomes in the GnomAD database, including 57,939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (57939 hom., cov: 31)
• Consequence: BMP5 NM_021073.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.989
• Publications: 4 publications found

Genes affected

BMP5 (HGNC:1072): (bone morphogenetic protein 5) 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, which plays a role in bone and cartilage development. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

BMP5 Gene-Disease associations (from GenCC):

• dysostosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP5	NM_021073.4	c.1028-6431C>T		intron_variant	Intron 4 of 6	ENST00000370830.4	NP_066551.1
BMP5	XM_011514817.4	c.*5901C>T		3_prime_UTR_variant	Exon 5 of 5		XP_011513119.1
BMP5	NM_001329754.2	c.1028-6431C>T		intron_variant	Intron 4 of 5		NP_001316683.1
BMP5	NM_001329756.2	c.1027+7085C>T		intron_variant	Intron 4 of 4		NP_001316685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.1028-6431C>T		intron_variant	Intron 4 of 6	1	NM_021073.4	ENSP00000359866.3

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132410 AN: 151914 Hom.: 57889 Cov.: 31

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.854

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.872 AC: 132513 AN: 152032 Hom.: 57939 Cov.: 31 AF XY: 0.869 AC XY: 64604 AN XY: 74316

African (AFR) AF: 0.939 AC: 39014 AN: 41548

American (AMR) AF: 0.852 AC: 12979 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2930 AN: 3472

East Asian (EAS) AF: 0.848 AC: 4356 AN: 5136

South Asian (SAS) AF: 0.791 AC: 3816 AN: 4824

European-Finnish (FIN) AF: 0.886 AC: 9398 AN: 10602

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57210 AN: 67912

Other (OTH) AF: 0.856 AC: 1805 AN: 2108

Alfa AF: 0.852 Hom.: 233444

Bravo AF: 0.876

Asia WGS AF: 0.836 AC: 2906 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs228144; hg19: chr6-55631762;