rs35211496

Variant names:

• chr18-62354528-C-T
• rs35211496
• NM_003839.4:c.421C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:6
• Conservation: PhyloP100: 2.23
• Publications: 42 publications found

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 Gene-Disease associations (from GenCC):

• Paget disease of bone 2, early-onset

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive osteopetrosis 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• familial expansile osteolysis

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dysosteosclerosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• osteosarcoma

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.421C>T	p.His141Tyr	missense	Exon 4 of 10	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.421C>T	p.His141Tyr	missense	Exon 4 of 10	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.421C>T	p.His141Tyr	missense	Exon 4 of 8	NP_001257879.1	Q9Y6Q6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.421C>T	p.His141Tyr	missense	Exon 4 of 10	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.421C>T	p.His141Tyr	missense	Exon 4 of 7	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.421C>T	p.His141Tyr	missense	Exon 4 of 10	ENSP00000573903.1

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

GnomAD2 exomes AF: 0.120 AC: 27699 AN: 230992 AF XY: 0.122

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 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

African (AFR) AF: 0.0267 AC: 894 AN: 33440

American (AMR) AF: 0.0912 AC: 4076 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4835 AN: 26086

East Asian (EAS) AF: 0.000681 AC: 27 AN: 39660

South Asian (SAS) AF: 0.0525 AC: 4523 AN: 86192

European-Finnish (FIN) AF: 0.115 AC: 4939 AN: 42942

Middle Eastern (MID) AF: 0.126 AC: 723 AN: 5738

European-Non Finnish (NFE) AF: 0.190 AC: 211507 AN: 1111226

Other (OTH) AF: 0.154 AC: 9276 AN: 60262

GnomAD4 genome AF: 0.121 AC: 18420 AN: 152298 Hom.: 1594 Cov.: 33 AF XY: 0.115 AC XY: 8594 AN XY: 74464

African (AFR) AF: 0.0324 AC: 1346 AN: 41592

American (AMR) AF: 0.118 AC: 1808 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5184

South Asian (SAS) AF: 0.0406 AC: 196 AN: 4830

European-Finnish (FIN) AF: 0.109 AC: 1156 AN: 10604

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.185 AC: 12603 AN: 67994

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.168 Hom.: 5211

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bone Paget disease (1)
-	-	1	Disorder of bone (1)
-	-	1	not specified (1)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.13
Sift	Benign	0.042	D
Sift4G	Uncertain	0.036	D
Polyphen		0.46	P
Vest4		0.26
MPC		2.2
ClinPred		0.024	T
GERP RS		3.1
Varity_R		0.29
gMVP		0.78
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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