8-118929038-A-G

Position:

• chr8-118929038-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.401-109T>C		intron_variant		ENST00000297350.9	NP_002537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.401-109T>C		intron_variant		1	NM_002546.4	ENSP00000297350	P1
TNFRSF11B	ENST00000517352.1	c.*244-109T>C		intron_variant, NMD_transcript_variant		1		ENSP00000427924
TNFRSF11B	ENST00000521597.1	n.36T>C		non_coding_transcript_exon_variant	1/3	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

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.276

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.460

Gnomad4 OTH exome AF: 0.389

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

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.325

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.367

Alfa AF: 0.407 Hom.: 1771

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	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

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: rs4876869; hg19: chr8-119941277; COSMIC: COSV52075035;