18-62360008-C-T

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.575C>T(p.Ala192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,612,518 control chromosomes in the GnomAD database, including 221,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A192A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.56 (24523 hom., cov: 32)
  • Exomes 𝑓: 0.52 (197394 hom.)
• Consequence: TNFRSF11A NM_003839.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.391

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 (MetaRNN=5.930566E-6).
• BP6: Variant 18-62360008-C-T is Benign according to our data. Variant chr18-62360008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-62360008-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF11A	NM_003839.4	c.575C>T	p.Ala192Val	missense_variant	6/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.575C>T	p.Ala192Val	missense_variant	6/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.575C>T	p.Ala192Val	missense_variant	6/7	1		A2
TNFRSF11A	ENST00000587697.1	n.493C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85554 AN: 151866 Hom.: 24478 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.600

GnomAD3 exomes AF: 0.545 AC: 136972 AN: 251466 Hom.: 38531 AF XY: 0.531 AC XY: 72180 AN XY: 135906

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.699

Gnomad SAS exome AF: 0.398

Gnomad FIN exome AF: 0.532

Gnomad NFE exome AF: 0.510

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.516 AC: 753844 AN: 1460534 Hom.: 197394 Cov.: 46 AF XY: 0.512 AC XY: 371717 AN XY: 726618

Gnomad4 AFR exome AF: 0.643

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.545

Gnomad4 EAS exome AF: 0.687

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.532

Gnomad4 NFE exome AF: 0.507

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.564 AC: 85661 AN: 151984 Hom.: 24523 Cov.: 32 AF XY: 0.565 AC XY: 41959 AN XY: 74308

Gnomad4 AFR AF: 0.640

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.691

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.596

Alfa AF: 0.523 Hom.: 54192

Bravo AF: 0.580

TwinsUK AF: 0.505 AC: 1872

ALSPAC AF: 0.528 AC: 2035

ESP6500AA AF: 0.632 AC: 2786

ESP6500EA AF: 0.511 AC: 4397

ExAC AF: 0.537 AC: 65161

Asia WGS AF: 0.569 AC: 1979 AN: 3478

EpiCase AF: 0.521

EpiControl AF: 0.524

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 20564239, 21987421) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Increased bone mineral density Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 17, 2022

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Benign	0.20
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.26	T;T;T;T;T
MetaRNN	Benign	0.0000059	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
Polyphen		0.012	.;.;.;.;B
Vest4		0.083, 0.067, 0.049
MPC		1.1
ClinPred		0.0027	T
GERP RS		2.6
Varity_R		0.024
gMVP		0.75

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: rs1805034; hg19: chr18-60027241; COSMIC: COSV54023702;