NM_003839.4:c.522-39T>A

Variant names:

• chr18-62359916-T-A
• rs6567271
• NM_003839.4:c.522-39T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003839.4(TNFRSF11A):​c.522-39T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,573,376 control chromosomes in the GnomAD database, including 215,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24568 hom., cov: 32)
  • Exomes 𝑓: 0.51 (191278 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.414
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-62359916-T-A is Benign according to our data. Variant chr18-62359916-T-A is described in ClinVar as Benign. ClinVar VariationId is 259181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.522-39T>A		intron_variant	Intron 5 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.522-39T>A		intron_variant	Intron 5 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.522-39T>A		intron_variant	Intron 5 of 6	1		ENSP00000269485.7
TNFRSF11A	ENST00000587697.1	n.440-39T>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85655 AN: 151912 Hom.: 24523 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.599

GnomAD2 exomes AF: 0.545 AC: 136885 AN: 251226 AF XY: 0.531

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.699

Gnomad FIN exome AF: 0.532

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.515 AC: 731533 AN: 1421346 Hom.: 191278 Cov.: 22 AF XY: 0.510 AC XY: 362105 AN XY: 709548

African (AFR) AF: 0.642 AC: 20911 AN: 32570

American (AMR) AF: 0.664 AC: 29614 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 14005 AN: 25832

East Asian (EAS) AF: 0.687 AC: 27025 AN: 39350

South Asian (SAS) AF: 0.398 AC: 34070 AN: 85536

European-Finnish (FIN) AF: 0.531 AC: 28216 AN: 53114

Middle Eastern (MID) AF: 0.516 AC: 2939 AN: 5698

European-Non Finnish (NFE) AF: 0.505 AC: 543613 AN: 1075620

Other (OTH) AF: 0.528 AC: 31140 AN: 59030

GnomAD4 genome AF: 0.564 AC: 85762 AN: 152030 Hom.: 24568 Cov.: 32 AF XY: 0.565 AC XY: 41996 AN XY: 74324

African (AFR) AF: 0.640 AC: 26529 AN: 41476

American (AMR) AF: 0.627 AC: 9580 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1889 AN: 3472

East Asian (EAS) AF: 0.692 AC: 3569 AN: 5160

South Asian (SAS) AF: 0.412 AC: 1986 AN: 4820

European-Finnish (FIN) AF: 0.529 AC: 5585 AN: 10560

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34754 AN: 67946

Other (OTH) AF: 0.595 AC: 1256 AN: 2112

Alfa AF: 0.529 Hom.: 3886

Bravo AF: 0.581

Asia WGS AF: 0.570 AC: 1980 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.71
PhyloP100		0.41
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: rs6567271; hg19: chr18-60027149; COSMIC: COSV54023681;