20-57171051-T-G

Position:

• chr20-57171051-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001719.3(BMP7):​c.1204A>C​(p.Asn402His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMP7 NM_001719.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

Genes affected

BMP7 (HGNC:1074): (bone morphogenetic protein 7) 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, kidney and brown adipose tissue development. Additionally, this protein induces ectopic bone formation and may promote fracture healing in human patients. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29333597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP7	NM_001719.3	c.1204A>C	p.Asn402His	missense_variant	7/7	ENST00000395863.8	NP_001710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP7	ENST00000395863.8	c.1204A>C	p.Asn402His	missense_variant	7/7	1	NM_001719.3	ENSP00000379204	P1
BMP7	ENST00000395864.7	c.1006A>C	p.Asn336His	missense_variant	6/6	5		ENSP00000379205
BMP7	ENST00000460817.5	n.704A>C		non_coding_transcript_exon_variant	6/6	3
BMP7	ENST00000476877.1	n.448A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The c.1204A>C (p.N402H) alteration is located in exon 7 (coding exon 7) of the BMP7 gene. This alteration results from a A to C substitution at nucleotide position 1204, causing the asparagine (N) at amino acid position 402 to be replaced by a histidine (H). 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	0.059
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.79	D;.
Eigen	Benign	-0.064
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.29
Sift	Benign	0.22	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0070	B;B
Vest4		0.16
MutPred		0.77		Gain of catalytic residue at L401 (P = 0.2472);.;
MVP		0.66
MPC		0.70
ClinPred		0.62	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-55746107;