18-62325314-G-A

Variant names:

• chr18-62325314-G-A
• rs7238731
• NM_003839.4:c.-39G>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.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 964,284 control chromosomes in the GnomAD database, including 34,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5996 hom., cov: 31)
  • Exomes 𝑓: 0.26 (28259 hom.)
• Consequence: TNFRSF11A NM_003839.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.25
• Publications: 6 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 (REVEL=0.012).
• BP6: Variant 18-62325314-G-A is Benign according to our data. Variant chr18-62325314-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 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.-39G>A		5_prime_UTR	Exon 1 of 10	NP_003830.1
	TNFRSF11A	NM_001278268.2		c.-39G>A		5_prime_UTR	Exon 1 of 10	NP_001265197.1
	TNFRSF11A	NM_001270950.2		c.-39G>A		5_prime_UTR	Exon 1 of 8	NP_001257879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.-39G>A		5_prime_UTR	Exon 1 of 10	ENSP00000465500.1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.-39G>A		5_prime_UTR	Exon 1 of 7	ENSP00000269485.7
	TNFRSF11A	ENST00000592013.1	TSL:2	n.-12G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.278 AC: 40719 AN: 146588 Hom.: 5994 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.0645 AC: 371 AN: 5752 AF XY: 0.0636

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0435

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.259 AC: 211770 AN: 817590 Hom.: 28259 Cov.: 13 AF XY: 0.258 AC XY: 98727 AN XY: 382418

African (AFR) AF: 0.334 AC: 5095 AN: 15242

American (AMR) AF: 0.108 AC: 319 AN: 2944

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 1116 AN: 5590

East Asian (EAS) AF: 0.0824 AC: 331 AN: 4018

South Asian (SAS) AF: 0.150 AC: 2852 AN: 18966

European-Finnish (FIN) AF: 0.178 AC: 173 AN: 972

Middle Eastern (MID) AF: 0.233 AC: 390 AN: 1674

European-Non Finnish (NFE) AF: 0.263 AC: 195073 AN: 741228

Other (OTH) AF: 0.238 AC: 6421 AN: 26956

GnomAD4 genome AF: 0.278 AC: 40733 AN: 146694 Hom.: 5996 Cov.: 31 AF XY: 0.273 AC XY: 19490 AN XY: 71404

African (AFR) AF: 0.343 AC: 14027 AN: 40906

American (AMR) AF: 0.228 AC: 3373 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 757 AN: 3388

East Asian (EAS) AF: 0.104 AC: 532 AN: 5112

South Asian (SAS) AF: 0.165 AC: 796 AN: 4820

European-Finnish (FIN) AF: 0.262 AC: 2245 AN: 8560

Middle Eastern (MID) AF: 0.250 AC: 72 AN: 288

European-Non Finnish (NFE) AF: 0.275 AC: 18098 AN: 65880

Other (OTH) AF: 0.274 AC: 560 AN: 2042

Alfa AF: 0.285 Hom.: 773

Bravo AF: 0.274

Asia WGS AF: 0.171 AC: 485 AN: 2834

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bone Paget disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteopetrosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.56
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		2.2
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7238731; hg19: chr18-59992547; COSMIC: COSV54025296; COSMIC: COSV54025296;