chr8-118929038-A-G

Variant names:

• chr8-118929038-A-G
• rs4876869
• NM_002546.4:c.401-109T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002546.4(TNFRSF11B):​c.401-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 933,470 control chromosomes in the GnomAD database, including 87,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11451 hom., cov: 33)
  • Exomes 𝑓: 0.43 (75566 hom.)
• Consequence: TNFRSF11B NM_002546.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.525
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-118929038-A-G is Benign according to our data. Variant chr8-118929038-A-G is described in ClinVar as Benign. ClinVar VariationId is 1297312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.401-109T>C		intron_variant	Intron 2 of 4	ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.401-109T>C		intron_variant	Intron 2 of 4	1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.*244-109T>C		intron_variant	Intron 3 of 4	1		ENSP00000427924.1
TNFRSF11B	ENST00000521597.1	n.36T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55256 AN: 152002 Hom.: 11444 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.429 AC: 335042 AN: 781350 Hom.: 75566 Cov.: 10 AF XY: 0.426 AC XY: 174702 AN XY: 410268

African (AFR) AF: 0.155 AC: 3083 AN: 19840

American (AMR) AF: 0.499 AC: 17906 AN: 35900

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 6620 AN: 20982

East Asian (EAS) AF: 0.276 AC: 9366 AN: 33986

South Asian (SAS) AF: 0.337 AC: 22679 AN: 67252

European-Finnish (FIN) AF: 0.487 AC: 20398 AN: 41856

Middle Eastern (MID) AF: 0.308 AC: 1116 AN: 3622

European-Non Finnish (NFE) AF: 0.460 AC: 239178 AN: 520090

Other (OTH) AF: 0.389 AC: 14696 AN: 37822

GnomAD4 genome AF: 0.363 AC: 55267 AN: 152120 Hom.: 11451 Cov.: 33 AF XY: 0.362 AC XY: 26906 AN XY: 74352

African (AFR) AF: 0.166 AC: 6871 AN: 41516

American (AMR) AF: 0.418 AC: 6392 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1325 AN: 5176

South Asian (SAS) AF: 0.325 AC: 1565 AN: 4816

European-Finnish (FIN) AF: 0.483 AC: 5101 AN: 10552

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31449 AN: 67974

Other (OTH) AF: 0.367 AC: 776 AN: 2114

Alfa AF: 0.314 Hom.: 2064

Bravo AF: 0.354

Asia WGS AF: 0.246 AC: 856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21994215) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.53
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: rs4876869; hg19: chr8-119941277; COSMIC: COSV52075035;