rs1805033

Variant names:

• chr18-62325344-T-C
• rs1805033
• NM_003839.4:c.-9T>C

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.-9T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,015,216 control chromosomes in the GnomAD database, including 37,933 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 (6061 hom., cov: 31)
  • Exomes 𝑓: 0.27 (31872 hom.)
• Consequence: TNFRSF11A NM_003839.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0360
• Publications: 7 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=0.007).
• BP6: Variant 18-62325344-T-C is Benign according to our data. Variant chr18-62325344-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 193259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.-9T>C		5_prime_UTR_variant	Exon 1 of 10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.-9T>C		5_prime_UTR_variant	Exon 1 of 10	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.-9T>C		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000269485.7
TNFRSF11A	ENST00000592013.1	n.19T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 40887 AN: 146526 Hom.: 6058 Cov.: 31

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.141 AC: 863 AN: 6136 AF XY: 0.133

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.267 AC: 231875 AN: 868590 Hom.: 31872 Cov.: 26 AF XY: 0.266 AC XY: 108782 AN XY: 408986

African (AFR) AF: 0.349 AC: 5684 AN: 16284

American (AMR) AF: 0.156 AC: 511 AN: 3286

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 1291 AN: 6154

East Asian (EAS) AF: 0.0920 AC: 444 AN: 4826

South Asian (SAS) AF: 0.160 AC: 3221 AN: 20070

European-Finnish (FIN) AF: 0.197 AC: 453 AN: 2298

Middle Eastern (MID) AF: 0.237 AC: 420 AN: 1770

European-Non Finnish (NFE) AF: 0.271 AC: 212755 AN: 784944

Other (OTH) AF: 0.245 AC: 7096 AN: 28958

GnomAD4 genome AF: 0.279 AC: 40902 AN: 146626 Hom.: 6061 Cov.: 31 AF XY: 0.274 AC XY: 19579 AN XY: 71374

African (AFR) AF: 0.346 AC: 14165 AN: 40902

American (AMR) AF: 0.229 AC: 3383 AN: 14794

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 757 AN: 3394

East Asian (EAS) AF: 0.105 AC: 535 AN: 5096

South Asian (SAS) AF: 0.167 AC: 798 AN: 4776

European-Finnish (FIN) AF: 0.262 AC: 2237 AN: 8528

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

European-Non Finnish (NFE) AF: 0.275 AC: 18119 AN: 65886

Other (OTH) AF: 0.274 AC: 562 AN: 2052

Alfa AF: 0.285 Hom.: 779

Bravo AF: 0.275

Asia WGS AF: 0.150 AC: 432 AN: 2880

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Aug 14, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		-0.036
PromoterAI		0.086	Neutral
Mutation Taster		=300/0	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: rs1805033; hg19: chr18-59992577;