rs35211496

Positions:

chr18-62354528-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.421C>T(p.His141Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,602,520 control chromosomes in the GnomAD database, including 23,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1594 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22160 hom. )

Consequence

TNFRSF11A
NM_003839.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.23

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=0.0013367832).

BP6

Variant 18-62354528-C-T is Benign according to our data. Variant chr18-62354528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 327729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 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.421C>T	p.His141Tyr	missense_variant	4/10	ENST00000586569.3	NP_003830.1	Q9Y6Q6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3 linkuse as main transcript	c.421C>T	p.His141Tyr	missense_variant	4/10	1	NM_003839.4	ENSP00000465500.1		Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 linkuse as main transcript	c.421C>T	p.His141Tyr	missense_variant	4/7	1		ENSP00000269485.7		Q9Y6Q6-2

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18419

AN:

152180

Hom.:

1595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0325

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0401

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.151

GnomAD3 exomes

AF:

0.120

AC:

27699

AN:

230992

Hom.:

2194

AF XY:

0.122

AC XY:

15474

AN XY:

127334

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.0871

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.000623

Gnomad SAS exome

AF:

0.0491

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.166

AC:

240800

AN:

1450222

Hom.:

22160

Cov.:

AF XY:

0.163

AC XY:

117815

AN XY:

721838

show subpopulations

Gnomad4 AFR exome

AF:

0.0267

Gnomad4 AMR exome

AF:

0.0912

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.000681

Gnomad4 SAS exome

AF:

0.0525

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.190

Gnomad4 OTH exome

AF:

0.154

GnomAD4 genome

AF:

0.121

AC:

18420

AN:

152298

Hom.:

1594

Cov.:

AF XY:

0.115

AC XY:

8594

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0324

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0406

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.185

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.171

Hom.:

3964

Bravo

AF:

0.119

TwinsUK

AF:

0.191

AC:

710

ALSPAC

AF:

0.197

AC:

758

ESP6500AA

AF:

0.0343

AC:

147

ESP6500EA

AF:

0.179

AC:

1506

ExAC

AF:

0.117

AC:

14056

Asia WGS

AF:

0.0510

AC:

178

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

not specified

Benign:1

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 -

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

0.095

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;.;.;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.0030

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;M;M;M;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.9

.;D;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.042

.;D;.;.;.

Sift4G

Uncertain

0.036

.;D;D;D;D

Polyphen

0.46

.;.;.;.;P

Vest4

0.26, 0.29, 0.22, 0.16

MPC

2.2

ClinPred

0.024

GERP RS

3.1

Varity_R

0.29

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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