18-62375584-C-T

Variant names:

• chr18-62375584-C-T
• rs4426449
• NM_003839.4:c.1567+6100C>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.1567+6100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,080 control chromosomes in the GnomAD database, including 5,959 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 0.26 (5959 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• 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

ENSG00000267341 (HGNC:):

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 = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.1567+6100C>T		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.1567+6100C>T		intron_variant	Intron 9 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.617-9167C>T		intron_variant	Intron 6 of 6	1		ENSP00000269485.7
ENSG00000267341	ENST00000589084.1	n.53-1437G>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40096 AN: 151962 Hom.: 5956 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0949

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.264 AC: 40127 AN: 152080 Hom.: 5959 Cov.: 32 AF XY: 0.258 AC XY: 19150 AN XY: 74332

African (AFR) AF: 0.181 AC: 7493 AN: 41480

American (AMR) AF: 0.295 AC: 4505 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3468

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5180

South Asian (SAS) AF: 0.0958 AC: 462 AN: 4822

European-Finnish (FIN) AF: 0.308 AC: 3254 AN: 10564

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.329 AC: 22369 AN: 67968

Other (OTH) AF: 0.290 AC: 612 AN: 2112

Alfa AF: 0.303 Hom.: 22396

Bravo AF: 0.264

Asia WGS AF: 0.100 AC: 350 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	3.0
DANN	Benign	0.48
PhyloP100		0.25
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: rs4426449; hg19: chr18-60042817;