rs6567271

chr18-62359916-T-Achr18-62359916-T-Cchr18-62359916-T-G

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.522-39T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,573,376 control chromosomes in the GnomAD database, including 215,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24568 hom., cov: 32)
  • Exomes 𝑓: 0.51 (191278 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.414

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=-0.88).
• BP6: Variant 18-62359916-T-A is Benign according to our data. Variant chr18-62359916-T-A is described in ClinVar as [Benign]. Clinvar id is 259181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.522-39T>A		intron_variant		ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.522-39T>A		intron_variant		1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.522-39T>A		intron_variant		1		A2
TNFRSF11A	ENST00000587697.1	n.440-39T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85655 AN: 151912 Hom.: 24523 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.545 AC: 136885 AN: 251226 Hom.: 38505 AF XY: 0.531 AC XY: 72151 AN XY: 135786

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.699

Gnomad SAS exome AF: 0.398

Gnomad FIN exome AF: 0.532

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.515 AC: 731533 AN: 1421346 Hom.: 191278 Cov.: 22 AF XY: 0.510 AC XY: 362105 AN XY: 709548

Gnomad4 AFR exome AF: 0.642

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.542

Gnomad4 EAS exome AF: 0.687

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.531

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.564 AC: 85762 AN: 152030 Hom.: 24568 Cov.: 32 AF XY: 0.565 AC XY: 41996 AN XY: 74324

Gnomad4 AFR AF: 0.640

Gnomad4 AMR AF: 0.627

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.595

Alfa AF: 0.529 Hom.: 3886

Bravo AF: 0.581

Asia WGS AF: 0.570 AC: 1980 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	7.0
Dann	Benign	0.71

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: rs6567271; hg19: chr18-60027149; COSMIC: COSV54023681;