18-62377435-T-C

Variant names:

• chr18-62377435-T-C
• rs6567276
• NM_003839.4:c.1568-7316T>C

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.1568-7316T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 152,002 control chromosomes in the GnomAD database, including 18,185 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 0.48 (18185 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.98
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive osteopetrosis 7

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

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

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

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

ENSG00000267341 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 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.1568-7316T>C		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.1526-7316T>C		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.731-7316T>C		intron	N/A	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.1568-7316T>C		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.617-7316T>C		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.1583-7316T>C		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73472 AN: 151884 Hom.: 18167 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.486

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

GnomAD4 genome AF: 0.484 AC: 73535 AN: 152002 Hom.: 18185 Cov.: 32 AF XY: 0.492 AC XY: 36544 AN XY: 74294

African (AFR) AF: 0.538 AC: 22313 AN: 41442

American (AMR) AF: 0.472 AC: 7211 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1813 AN: 3468

East Asian (EAS) AF: 0.694 AC: 3583 AN: 5166

South Asian (SAS) AF: 0.611 AC: 2946 AN: 4822

European-Finnish (FIN) AF: 0.504 AC: 5321 AN: 10554

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28783 AN: 67962

Other (OTH) AF: 0.480 AC: 1014 AN: 2114

Alfa AF: 0.435 Hom.: 31628

Bravo AF: 0.483

Asia WGS AF: 0.626 AC: 2175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.33
DANN	Benign	0.35
PhyloP100		-3.0
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: rs6567276; hg19: chr18-60044668;