chr18-62384709-G-T

Variant names:

• chr18-62384709-G-T
• rs77857469
• NM_003839.4:c.1568-42G>T

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.1568-42G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,600,796 control chromosomes in the GnomAD database, including 3,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (793 hom., cov: 30)
  • Exomes 𝑓: 0.056 (2832 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.340
• Publications: 3 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=-0.77).
• BP6: Variant 18-62384709-G-T is Benign according to our data. Variant chr18-62384709-G-T is described in ClinVar as Benign. ClinVar VariationId is 259178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.1568-42G>T		intron	N/A	NP_003830.1
	TNFRSF11A	NM_001278268.2		c.1526-42G>T		intron	N/A	NP_001265197.1
	TNFRSF11A	NM_001270950.2		c.731-42G>T		intron	N/A	NP_001257879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.1568-42G>T		intron	N/A	ENSP00000465500.1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.617-42G>T		intron	N/A	ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13241 AN: 151468 Hom.: 790 Cov.: 30

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0707

Gnomad ASJ AF: 0.0736

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0577

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0627

GnomAD2 exomes AF: 0.0728 AC: 16784 AN: 230622 AF XY: 0.0674

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0678

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.0597

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0565 AC: 81837 AN: 1449210 Hom.: 2832 Cov.: 32 AF XY: 0.0556 AC XY: 40000 AN XY: 719594

African (AFR) AF: 0.166 AC: 5515 AN: 33270

American (AMR) AF: 0.114 AC: 4965 AN: 43506

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1731 AN: 25804

East Asian (EAS) AF: 0.000254 AC: 10 AN: 39388

South Asian (SAS) AF: 0.0538 AC: 4510 AN: 83852

European-Finnish (FIN) AF: 0.0927 AC: 4873 AN: 52588

Middle Eastern (MID) AF: 0.0406 AC: 233 AN: 5736

European-Non Finnish (NFE) AF: 0.0512 AC: 56534 AN: 1105190

Other (OTH) AF: 0.0579 AC: 3466 AN: 59876

GnomAD4 genome AF: 0.0875 AC: 13270 AN: 151586 Hom.: 793 Cov.: 30 AF XY: 0.0869 AC XY: 6439 AN XY: 74072

African (AFR) AF: 0.165 AC: 6832 AN: 41302

American (AMR) AF: 0.0709 AC: 1082 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 255 AN: 3466

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5090

South Asian (SAS) AF: 0.0559 AC: 268 AN: 4796

European-Finnish (FIN) AF: 0.0888 AC: 937 AN: 10550

Middle Eastern (MID) AF: 0.0586 AC: 17 AN: 290

European-Non Finnish (NFE) AF: 0.0549 AC: 3726 AN: 67828

Other (OTH) AF: 0.0621 AC: 130 AN: 2094

Alfa AF: 0.0728 Hom.: 89

Bravo AF: 0.0910

Asia WGS AF: 0.0300 AC: 105 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

Jun 19, 2021

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		-0.34
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: rs77857469; hg19: chr18-60051942;