NM_003839.4:c.522-17C>T

Variant names:

• chr18-62359938-C-T
• rs6567272
• NM_003839.4:c.522-17C>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.522-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,607,418 control chromosomes in the GnomAD database, including 221,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24553 hom., cov: 32)
  • Exomes 𝑓: 0.52 (197258 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0790
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive osteopetrosis 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• familial expansile osteolysis

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• 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=-0.92).
• BP6: Variant 18-62359938-C-T is Benign according to our data. Variant chr18-62359938-C-T is described in ClinVar as Benign. ClinVar VariationId is 259180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.522-17C>T		intron	N/A	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.480-17C>T		intron	N/A	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.522-17C>T		intron	N/A	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.522-17C>T		intron	N/A	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.522-17C>T		intron	N/A	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.537-17C>T		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85624 AN: 151878 Hom.: 24508 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.600

GnomAD2 exomes AF: 0.545 AC: 137045 AN: 251422 AF XY: 0.532

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.551

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: 0.517 AC: 752139 AN: 1455422 Hom.: 197258 Cov.: 29 AF XY: 0.512 AC XY: 371081 AN XY: 724410

African (AFR) AF: 0.643 AC: 21440 AN: 33334

American (AMR) AF: 0.664 AC: 29669 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 14194 AN: 26074

East Asian (EAS) AF: 0.687 AC: 27243 AN: 39642

South Asian (SAS) AF: 0.399 AC: 34375 AN: 86126

European-Finnish (FIN) AF: 0.532 AC: 28329 AN: 53290

Middle Eastern (MID) AF: 0.515 AC: 2962 AN: 5750

European-Non Finnish (NFE) AF: 0.508 AC: 562081 AN: 1106348

Other (OTH) AF: 0.529 AC: 31846 AN: 60178

GnomAD4 genome AF: 0.564 AC: 85731 AN: 151996 Hom.: 24553 Cov.: 32 AF XY: 0.565 AC XY: 41969 AN XY: 74294

African (AFR) AF: 0.640 AC: 26506 AN: 41444

American (AMR) AF: 0.627 AC: 9576 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1892 AN: 3472

East Asian (EAS) AF: 0.691 AC: 3565 AN: 5156

South Asian (SAS) AF: 0.412 AC: 1986 AN: 4824

European-Finnish (FIN) AF: 0.529 AC: 5578 AN: 10548

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

European-Non Finnish (NFE) AF: 0.511 AC: 34757 AN: 67954

Other (OTH) AF: 0.595 AC: 1257 AN: 2112

Alfa AF: 0.532 Hom.: 83551

Bravo AF: 0.581

Asia WGS AF: 0.569 AC: 1979 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.44
PhyloP100		-0.079
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: rs6567272; hg19: chr18-60027171; COSMIC: COSV54023692;