18-62383966-C-G

Variant names:

• chr18-62383966-C-G
• rs9646629
• NM_003839.4:c.1568-785C>G

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.1568-785C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 151,792 control chromosomes in the GnomAD database, including 34,295 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 0.67 (34295 hom., cov: 29)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.1568-785C>G		intron_variant	Intron 9 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.1568-785C>G		intron_variant	Intron 9 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.617-785C>G		intron_variant	Intron 6 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101481 AN: 151672 Hom.: 34255 Cov.: 29

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.657

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

GnomAD4 genome AF: 0.669 AC: 101577 AN: 151792 Hom.: 34295 Cov.: 29 AF XY: 0.667 AC XY: 49484 AN XY: 74166

African (AFR) AF: 0.743 AC: 30737 AN: 41348

American (AMR) AF: 0.698 AC: 10652 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2258 AN: 3468

East Asian (EAS) AF: 0.552 AC: 2842 AN: 5150

South Asian (SAS) AF: 0.594 AC: 2849 AN: 4796

European-Finnish (FIN) AF: 0.653 AC: 6875 AN: 10530

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43253 AN: 67924

Other (OTH) AF: 0.661 AC: 1393 AN: 2108

Alfa AF: 0.520 Hom.: 1387

Bravo AF: 0.676

Asia WGS AF: 0.573 AC: 1994 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.36
PhyloP100		-0.32
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: rs9646629; hg19: chr18-60051199;