chr6-55774120-T-C

Variant names:

• chr6-55774120-T-C
• rs144630424
• NM_021073.4:c.956A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021073.4(BMP5):​c.956A>G​(p.Asn319Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,170 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: BMP5 NM_021073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014367133).
• BS2: High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP5	NM_021073.4	c.956A>G	p.Asn319Ser	missense_variant	Exon 4 of 7	ENST00000370830.4	NP_066551.1
BMP5	NM_001329754.2	c.956A>G	p.Asn319Ser	missense_variant	Exon 4 of 6		NP_001316683.1
BMP5	NM_001329756.2	c.956A>G	p.Asn319Ser	missense_variant	Exon 4 of 5		NP_001316685.1
BMP5	XM_011514817.4	c.956A>G	p.Asn319Ser	missense_variant	Exon 4 of 5		XP_011513119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP5	ENST00000370830.4	c.956A>G	p.Asn319Ser	missense_variant	Exon 4 of 7	1	NM_021073.4	ENSP00000359866.3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 151924 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00110 AC: 276 AN: 251296 Hom.: 2 AF XY: 0.00103 AC XY: 140 AN XY: 135816

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00159 AC: 2330 AN: 1461128 Hom.: 2 Cov.: 31 AF XY: 0.00152 AC XY: 1106 AN XY: 726890

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152042 Hom.: 1 Cov.: 32 AF XY: 0.000848 AC XY: 63 AN XY: 74332

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00128 AC: 156

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.956A>G (p.N319S) alteration is located in exon 4 (coding exon 4) of the BMP5 gene. This alteration results from a A to G substitution at nucleotide position 956, causing the asparagine (N) at amino acid position 319 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.75	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.097
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.60
MPC		0.16
ClinPred		0.0042	T
GERP RS		3.3
Varity_R		0.030
gMVP		0.18

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: rs144630424; hg19: chr6-55638918;