rs10505346

Variant names:

• chr8-118951604-G-T
• rs10505346
• NM_002546.4:c.30+188C>A

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.30+188C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,038 control chromosomes in the GnomAD database, including 4,121 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 0.22 (4121 hom., cov: 32)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165
• Publications: 19 publications found

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]

TNFRSF11B Gene-Disease associations (from GenCC):

• juvenile Paget disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.30+188C>A		intron_variant	Intron 1 of 4	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.30+188C>A		intron_variant	Intron 1 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.30+188C>A		intron_variant	Intron 1 of 4	1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33790 AN: 151920 Hom.: 4108 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.223 AC: 33845 AN: 152038 Hom.: 4121 Cov.: 32 AF XY: 0.218 AC XY: 16177 AN XY: 74314

African (AFR) AF: 0.320 AC: 13278 AN: 41446

American (AMR) AF: 0.193 AC: 2957 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3466

East Asian (EAS) AF: 0.135 AC: 698 AN: 5154

South Asian (SAS) AF: 0.210 AC: 1011 AN: 4820

European-Finnish (FIN) AF: 0.127 AC: 1345 AN: 10578

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.192 AC: 13034 AN: 67984

Other (OTH) AF: 0.245 AC: 516 AN: 2104

Alfa AF: 0.202 Hom.: 14284

Bravo AF: 0.231

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.58
PhyloP100		-0.17
PromoterAI		-0.022	Neutral
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: rs10505346; hg19: chr8-119963843;