Genetic Variant TNFRSF11A:c.1568-42G>T (chr18-62384709-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003839.4(TNFRSF11A):c.1568-42G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,600,796 control chromosomes in the GnomAD database, including 3,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 793 hom., cov: 30)

Exomes 𝑓: 0.056 ( 2832 hom. )

Consequence

TNFRSF11A
NM_003839.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.340

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 18-62384709-G-T is Benign according to our data. Variant chr18-62384709-G-T is described in ClinVar as [Benign]. Clinvar id is 259178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.1568-42G>T		intron_variant	Intron 9 of 9	ENST00000586569.3	NP_003830.1	Q9Y6Q6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3 link	c.1568-42G>T		intron_variant	Intron 9 of 9	1	NM_003839.4	ENSP00000465500.1		Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.617-42G>T		intron_variant	Intron 6 of 6	1		ENSP00000269485.7		Q9Y6Q6-2

Frequencies

GnomAD3 genomes

AF:

0.0874

AC:

13241

AN:

151468

Hom.:

790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0707

Gnomad ASJ

AF:

0.0736

Gnomad EAS

AF:

0.000392

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.0888

Gnomad MID

AF:

0.0577

Gnomad NFE

AF:

0.0549

Gnomad OTH

AF:

0.0627

GnomAD3 exomes

AF:

0.0728

AC:

16784

AN:

230622

Hom.:

819

AF XY:

0.0674

AC XY:

8402

AN XY:

124568

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0678

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0529

Gnomad FIN exome

AF:

0.0905

Gnomad NFE exome

AF:

0.0597

Gnomad OTH exome

AF:

0.0566

GnomAD4 exome

AF:

0.0565

AC:

81837

AN:

1449210

Hom.:

2832

Cov.:

AF XY:

0.0556

AC XY:

40000

AN XY:

719594

show subpopulations

Gnomad4 AFR exome

AF:

0.166

Gnomad4 AMR exome

AF:

0.114

Gnomad4 ASJ exome

AF:

0.0671

Gnomad4 EAS exome

AF:

0.000254

Gnomad4 SAS exome

AF:

0.0538

Gnomad4 FIN exome

AF:

0.0927

Gnomad4 NFE exome

AF:

0.0512

Gnomad4 OTH exome

AF:

0.0579

GnomAD4 genome

AF:

0.0875

AC:

13270

AN:

151586

Hom.:

793

Cov.:

AF XY:

0.0869

AC XY:

6439

AN XY:

74072

show subpopulations

Gnomad4 AFR

AF:

0.165

Gnomad4 AMR

AF:

0.0709

Gnomad4 ASJ

AF:

0.0736

Gnomad4 EAS

AF:

0.000589

Gnomad4 SAS

AF:

0.0559

Gnomad4 FIN

AF:

0.0888

Gnomad4 NFE

AF:

0.0549

Gnomad4 OTH

AF:

0.0621

Alfa

AF:

0.0728

Hom.:

Bravo

AF:

0.0910

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: 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

-0.77

CADD

Benign

DANN

Benign

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over