rs7238731

chr18-62325314-G-A

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 18-62325314-G-A is Benign according to our data. Variant chr18-62325314-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.-39G>A		5_prime_UTR_variant	1/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.-39G>A		5_prime_UTR_variant	1/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.-39G>A		5_prime_UTR_variant	1/7	1		A2
TNFRSF11A	ENST00000592013.1			upstream_gene_variant		2

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

GnomAD3 exomes AF: 0.0645 AC: 371 AN: 5752 Hom.: 14 AF XY: 0.0636 AC XY: 202 AN XY: 3178

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 SAS exome AF: 0.0396

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

Gnomad4 AFR exome AF: 0.334

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.0824

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.263

Gnomad4 OTH exome AF: 0.238

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

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.274

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bone Paget disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Osteopetrosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

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

Publications

LitVar

Other links and lift over

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