rs35211496

chr18-62354528-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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. H141H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1594 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22160 hom.)
• Consequence: TNFRSF11A NM_003839.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.23

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=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	UniProt
TNFRSF11A	NM_003839.4	c.421C>T	p.His141Tyr	missense_variant	4/10	ENST00000586569.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.421C>T	p.His141Tyr	missense_variant	4/10	1	NM_003839.4	P2
TNFRSF11A	ENST00000269485.11	c.421C>T	p.His141Tyr	missense_variant	4/7	1		A2

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18419 AN: 152180 Hom.: 1595 Cov.: 33

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

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.: 33 AF XY: 0.163 AC XY: 117815 AN XY: 721838

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.: 33 AF XY: 0.115 AC XY: 8594 AN XY: 74464

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	P;P
PrimateAI	Benign	0.39	T
Polyphen		0.46	.;.;.;.;P
Vest4		0.26, 0.29, 0.22, 0.16
MPC		2.2
ClinPred		0.024	T
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

Other links and lift over

dbSNP: rs35211496; hg19: chr18-60021761; COSMIC: COSV54021662; COSMIC: COSV54021662;