rs12458117

Variant names:

• chr18-62360215-G-A
• rs12458117
• NM_003839.4:c.616+166G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-62360215-G-A
• chr18-62360215-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003839.4(TNFRSF11A):​c.616+166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,030 control chromosomes in the GnomAD database, including 1,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1346 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.75
• Publications: 14 publications found

Genes affected

TNFRSF11A (HGNC:11908): (TNF receptor superfamily member 11a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptors can interact with various TRAF family proteins, through which this receptor induces the activation of NF-kappa B and MAPK8/JNK. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Paget disease of bone. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2012]

TNFRSF11A Gene-Disease associations (from GenCC):

• Paget disease of bone 2, early-onset

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive osteopetrosis 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• familial expansile osteolysis

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• osteosarcoma

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-62360215-G-A is Benign according to our data. Variant chr18-62360215-G-A is described in ClinVar as Benign. ClinVar VariationId is 1220751.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.616+166G>A		intron_variant	Intron 6 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.616+166G>A		intron_variant	Intron 6 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.616+166G>A		intron_variant	Intron 6 of 6	1		ENSP00000269485.7
TNFRSF11A	ENST00000587697.1	n.*172G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18124 AN: 151914 Hom.: 1343 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.119 AC: 18139 AN: 152030 Hom.: 1346 Cov.: 32 AF XY: 0.125 AC XY: 9305 AN XY: 74332

African (AFR) AF: 0.0402 AC: 1668 AN: 41468

American (AMR) AF: 0.147 AC: 2252 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 585 AN: 3464

East Asian (EAS) AF: 0.301 AC: 1556 AN: 5166

South Asian (SAS) AF: 0.142 AC: 685 AN: 4826

European-Finnish (FIN) AF: 0.194 AC: 2046 AN: 10558

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.131 AC: 8923 AN: 67958

Other (OTH) AF: 0.143 AC: 301 AN: 2110

Alfa AF: 0.124 Hom.: 2447

Bravo AF: 0.113

Asia WGS AF: 0.216 AC: 748 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.80
PhyloP100		-1.7
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: rs12458117; hg19: chr18-60027448;