8-118933105-T-G

Position:

• chr8-118933105-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002546.4(TNFRSF11B):​c.226A>C​(p.Thr76Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11B NM_002546.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.58

Genes affected

TNFRSF11B (HGNC:11909): (TNF receptor superfamily member 11b) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-118933105-T-G is Pathogenic according to our data. Variant chr8-118933105-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 208809.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.226A>C	p.Thr76Pro	missense_variant	2/5	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.226A>C	p.Thr76Pro	missense_variant	2/5	1	NM_002546.4	ENSP00000297350	P1
TNFRSF11B	ENST00000517352.1	c.226A>C	p.Thr76Pro	missense_variant, NMD_transcript_variant	2/5	1		ENSP00000427924

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperphosphatasemia with bone disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.53	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.76
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Polyphen		0.14	B
Vest4		0.72
MutPred		0.48		Gain of disorder (P = 0.1186);
MVP		0.81
MPC		0.45
ClinPred		0.41	T
GERP RS		3.7
Varity_R		0.76
gMVP		0.74

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: rs200071478; hg19: chr8-119945344;