rs4603673

Variant names:

• chr18-62335641-C-G
• rs4603673
• NM_003839.4:c.75+10214C>G

Your query was ambiguous. Multiple possible variants found:

• chr18-62335641-C-G
• chr18-62335641-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+10214C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 152,222 control chromosomes in the GnomAD database, including 140 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 0.016 (140 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.75+10214C>G		intron	N/A	NP_003830.1
	TNFRSF11A	NM_001278268.2		c.75+10214C>G		intron	N/A	NP_001265197.1
	TNFRSF11A	NM_001270950.2		c.75+10214C>G		intron	N/A	NP_001257879.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.75+10214C>G		intron	N/A	ENSP00000465500.1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.75+10214C>G		intron	N/A	ENSP00000269485.7
	TNFRSF11A	ENST00000903844.1		c.75+10214C>G		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2482 AN: 152104 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0969

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.0125

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

GnomAD4 genome AF: 0.0163 AC: 2481 AN: 152222 Hom.: 140 Cov.: 32 AF XY: 0.0193 AC XY: 1438 AN XY: 74424

African (AFR) AF: 0.00289 AC: 120 AN: 41532

American (AMR) AF: 0.0516 AC: 790 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.174 AC: 898 AN: 5152

South Asian (SAS) AF: 0.0968 AC: 466 AN: 4816

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 68020

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.0206

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.66
DANN	Benign	0.65
PhyloP100		-1.2
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: rs4603673; hg19: chr18-60002874;