18-62354271-T-G

Variant names:

• chr18-62354271-T-G
• rs3826620
• NM_003839.4:c.284-120T>G

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.284-120T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,291,782 control chromosomes in the GnomAD database, including 321,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37052 hom., cov: 33)
  • Exomes 𝑓: 0.71 (284616 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70
• Publications: 22 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=-0.83).
• BP6: Variant 18-62354271-T-G is Benign according to our data. Variant chr18-62354271-T-G is described in ClinVar as Benign. ClinVar VariationId is 1276240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.284-120T>G		intron_variant	Intron 3 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.284-120T>G		intron_variant	Intron 3 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.284-120T>G		intron_variant	Intron 3 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105757 AN: 152034 Hom.: 37008 Cov.: 33

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.697

GnomAD4 exome AF: 0.706 AC: 804137 AN: 1139630 Hom.: 284616 AF XY: 0.705 AC XY: 391478 AN XY: 555314

African (AFR) AF: 0.678 AC: 16743 AN: 24686

American (AMR) AF: 0.617 AC: 12114 AN: 19644

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 13250 AN: 17754

East Asian (EAS) AF: 0.560 AC: 18150 AN: 32410

South Asian (SAS) AF: 0.658 AC: 37298 AN: 56710

European-Finnish (FIN) AF: 0.735 AC: 22343 AN: 30394

Middle Eastern (MID) AF: 0.706 AC: 2349 AN: 3326

European-Non Finnish (NFE) AF: 0.715 AC: 647798 AN: 906262

Other (OTH) AF: 0.704 AC: 34092 AN: 48444

GnomAD4 genome AF: 0.696 AC: 105856 AN: 152152 Hom.: 37052 Cov.: 33 AF XY: 0.696 AC XY: 51778 AN XY: 74370

African (AFR) AF: 0.681 AC: 28249 AN: 41510

American (AMR) AF: 0.646 AC: 9881 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2594 AN: 3470

East Asian (EAS) AF: 0.605 AC: 3120 AN: 5158

South Asian (SAS) AF: 0.651 AC: 3140 AN: 4822

European-Finnish (FIN) AF: 0.736 AC: 7809 AN: 10604

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48705 AN: 67976

Other (OTH) AF: 0.694 AC: 1466 AN: 2112

Alfa AF: 0.703 Hom.: 155207

Bravo AF: 0.684

Asia WGS AF: 0.651 AC: 2265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.73
PhyloP100		-2.7
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: rs3826620; hg19: chr18-60021504; COSMIC: COSV107203252; COSMIC: COSV107203252;