NM_003839.4:c.*5074T>A

Variant names:

• chr18-62390108-T-A
• rs17665435
• NM_003839.4:c.*5074T>A

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.*5074T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,160 control chromosomes in the GnomAD database, including 5,867 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 (5866 hom., cov: 32)
  • Exomes 𝑓: 0.36 (1 hom.)
• Consequence: TNFRSF11A NM_003839.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.878
• Publications: 10 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.*5074T>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.*5074T>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_003839.4	ENSP00000465500.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40075 AN: 152008 Hom.: 5861 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.0731

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.361 AC: 13 AN: 36 Hom.: 1 Cov.: 0 AF XY: 0.250 AC XY: 5 AN XY: 20

African (AFR) AF: 0.00 AC: 0 AN: 2

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) AF: 0.500 AC: 6 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.389 AC: 7 AN: 18

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.264 AC: 40125 AN: 152124 Hom.: 5866 Cov.: 32 AF XY: 0.259 AC XY: 19279 AN XY: 74360

African (AFR) AF: 0.161 AC: 6696 AN: 41512

American (AMR) AF: 0.280 AC: 4273 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.0734 AC: 380 AN: 5176

South Asian (SAS) AF: 0.174 AC: 839 AN: 4824

European-Finnish (FIN) AF: 0.319 AC: 3371 AN: 10576

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22440 AN: 67964

Other (OTH) AF: 0.278 AC: 588 AN: 2114

Alfa AF: 0.197 Hom.: 454

Bravo AF: 0.258

Asia WGS AF: 0.168 AC: 588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.89
PhyloP100		0.88
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: rs17665435; hg19: chr18-60057341;