rs8092336

Positions:

• chr18-62368850-A-G
• chr18-62368850-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003839.4(TNFRSF11A):​c.933A>G​(p.Thr311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,614,226 control chromosomes in the GnomAD database, including 719,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70187 hom., cov: 32)
  • Exomes 𝑓: 0.94 (649501 hom.)
• Consequence: TNFRSF11A NM_003839.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-62368850-A-G is Benign according to our data. Variant chr18-62368850-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62368850-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.933A>G	p.Thr311=	synonymous_variant	9/10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.933A>G	p.Thr311=	synonymous_variant	9/10	1	NM_003839.4	ENSP00000465500	P2
TNFRSF11A	ENST00000269485.11	c.616+8801A>G		intron_variant		1		ENSP00000269485	A2

Frequencies

GnomAD3 genomes AF: 0.960 AC: 146061 AN: 152222 Hom.: 70123 Cov.: 32

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.961

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.965

GnomAD3 exomes AF: 0.958 AC: 240889 AN: 251488 Hom.: 115447 AF XY: 0.956 AC XY: 129872 AN XY: 135918

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.961

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.960

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.937

Gnomad OTH exome AF: 0.957

GnomAD4 exome AF: 0.942 AC: 1377626 AN: 1461886 Hom.: 649501 Cov.: 92 AF XY: 0.942 AC XY: 685410 AN XY: 727242

Gnomad4 AFR exome AF: 0.992

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.961

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.961

Gnomad4 NFE exome AF: 0.934

Gnomad4 OTH exome AF: 0.948

GnomAD4 genome AF: 0.960 AC: 146183 AN: 152340 Hom.: 70187 Cov.: 32 AF XY: 0.962 AC XY: 71627 AN XY: 74488

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.974

Gnomad4 ASJ AF: 0.960

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.961

Gnomad4 FIN AF: 0.960

Gnomad4 NFE AF: 0.935

Gnomad4 OTH AF: 0.966

Alfa AF: 0.944 Hom.: 110330

Bravo AF: 0.964

Asia WGS AF: 0.986 AC: 3429 AN: 3478

EpiCase AF: 0.941

EpiControl AF: 0.940

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: MAF -

Familial expansile osteolysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Bone Paget disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Osteopetrosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive osteopetrosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.30

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: rs8092336; hg19: chr18-60036083;