rs4436867

Variant names:

• chr18-62336411-C-A
• rs4436867
• NM_003839.4:c.75+10984C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-62336411-C-A
• chr18-62336411-C-T

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.75+10984C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,202 control chromosomes in the GnomAD database, including 2,380 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 0.15 (2379 hom., cov: 32)
  • Exomes 𝑓: 0.25 (1 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.75+10984C>A		intron_variant	Intron 1 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.75+10984C>A		intron_variant	Intron 1 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.75+10984C>A		intron_variant	Intron 1 of 6	1		ENSP00000269485.7
TNFRSF11A	ENST00000592013.1	n.200C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23073 AN: 152048 Hom.: 2379 Cov.: 32

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.173

GnomAD4 exome AF: 0.250 AC: 9 AN: 36 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 8 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.219 AC: 7 AN: 32

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.152 AC: 23081 AN: 152166 Hom.: 2379 Cov.: 32 AF XY: 0.150 AC XY: 11139 AN XY: 74362

African (AFR) AF: 0.0389 AC: 1616 AN: 41552

American (AMR) AF: 0.140 AC: 2137 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 789 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.107 AC: 515 AN: 4818

European-Finnish (FIN) AF: 0.216 AC: 2278 AN: 10568

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.222 AC: 15069 AN: 67990

Other (OTH) AF: 0.175 AC: 370 AN: 2110

Alfa AF: 0.0643 Hom.: 100

Bravo AF: 0.142

Asia WGS AF: 0.0670 AC: 235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.45
PhyloP100		-0.075
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: rs4436867; hg19: chr18-60003644;