18-62354271-T-G

Position:

• chr18-62354271-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.284-120T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,291,782 control chromosomes in the GnomAD database, including 321,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37052 hom., cov: 33)
  • Exomes 𝑓: 0.71 (284616 hom.)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70

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=-0.83).
• BP6: Variant 18-62354271-T-G is Benign according to our data. Variant chr18-62354271-T-G is described in ClinVar as [Benign]. Clinvar id is 1276240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.284-120T>G		intron_variant		ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.284-120T>G		intron_variant		1	NM_003839.4	ENSP00000465500	P2
TNFRSF11A	ENST00000269485.11	c.284-120T>G		intron_variant		1		ENSP00000269485	A2

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105757 AN: 152034 Hom.: 37008 Cov.: 33

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.697

GnomAD4 exome AF: 0.706 AC: 804137 AN: 1139630 Hom.: 284616 AF XY: 0.705 AC XY: 391478 AN XY: 555314

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.617

Gnomad4 ASJ exome AF: 0.746

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.658

Gnomad4 FIN exome AF: 0.735

Gnomad4 NFE exome AF: 0.715

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.696 AC: 105856 AN: 152152 Hom.: 37052 Cov.: 33 AF XY: 0.696 AC XY: 51778 AN XY: 74370

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.646

Gnomad4 ASJ AF: 0.748

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.694

Alfa AF: 0.705 Hom.: 74230

Bravo AF: 0.684

Asia WGS AF: 0.651 AC: 2265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.73

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: rs3826620; hg19: chr18-60021504;