chr18-62360008-C-T

Position:

chr18-62360008-C-T

Variant summary

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

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 (★★).

Frequency

Genomes: 𝑓 0.56 ( 24523 hom., cov: 32)

Exomes 𝑓: 0.52 ( 197394 hom. )

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.391

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
TNFRSF11A	NM_003839.4 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/10	1	NM_003839.4	ENSP00000465500	P2	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 linkuse as main transcript	c.575C>T	p.Ala192Val	missense_variant	6/7	1		ENSP00000269485	A2	Q9Y6Q6-2
TNFRSF11A	ENST00000587697.1 linkuse as main transcript	n.493C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.563

AC:

85554

AN:

151866

Hom.:

24478

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.512

AC XY:

371717

AN XY:

726618

show subpopulations

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.:

AF XY:

0.565

AC XY:

41959

AN XY:

74308

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 20564239, 21987421) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.20

DEOGEN2

Benign

0.14

.;.;.;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.26

T;T;T;T;T

MetaRNN

Benign

0.0000059

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.81

.;N;N;N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

1.4

.;N;.;.;.

REVEL

Benign

0.047

Sift

Benign

1.0

.;T;.;.;.

Sift4G

Benign

1.0

.;T;T;T;T

Polyphen

0.012

.;.;.;.;B

Vest4

0.083, 0.067, 0.049

MPC

1.1

ClinPred

0.0027

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

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