rs884205

Positions:

• chr18-62387624-A-C
• chr18-62387624-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000586569.3(TNFRSF11A):​c.*2590A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 152,196 control chromosomes in the GnomAD database, including 50,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50812 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TNFRSF11A ENST00000586569.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.362

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=-0.89).
• BP6: Variant 18-62387624-A-C is Benign according to our data. Variant chr18-62387624-A-C is described in ClinVar as [Benign]. Clinvar id is 891660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.*2590A>C		3_prime_UTR_variant	10/10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.*2590A>C		3_prime_UTR_variant	10/10	1	NM_003839.4	ENSP00000465500	P2
TNFRSF11A	ENST00000269485.11	c.*2590A>C		3_prime_UTR_variant	7/7	1		ENSP00000269485	A2

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123468 AN: 152076 Hom.: 50746 Cov.: 32

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.827

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.812 AC: 123590 AN: 152196 Hom.: 50812 Cov.: 32 AF XY: 0.811 AC XY: 60340 AN XY: 74396

Gnomad4 AFR AF: 0.939

Gnomad4 AMR AF: 0.828

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.749

Gnomad4 OTH AF: 0.831

Alfa AF: 0.768 Hom.: 78732

Bravo AF: 0.827

Asia WGS AF: 0.786 AC: 2735 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Paget disease of bone 2, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive osteopetrosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs884205; hg19: chr18-60054857;