NM_003839.4:c.575C>T

Variant names:

• chr18-62360008-C-T
• rs1805034
• NM_003839.4:c.575C>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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A192E) has been classified as Uncertain significance.

• 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:8
• Conservation: PhyloP100: 0.391
• Publications: 111 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=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 Benign/Likely_benign. ClinVar VariationId is 259182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 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.575C>T	p.Ala192Val	missense	Exon 6 of 10	NP_003830.1	Q9Y6Q6-1
	TNFRSF11A	NM_001278268.2		c.533C>T	p.Ala178Val	missense	Exon 6 of 10	NP_001265197.1	Q9Y6Q6-6
	TNFRSF11A	NM_001270950.2		c.575C>T	p.Ala192Val	missense	Exon 6 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.575C>T	p.Ala192Val	missense	Exon 6 of 10	ENSP00000465500.1	Q9Y6Q6-1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.575C>T	p.Ala192Val	missense	Exon 6 of 7	ENSP00000269485.7	Q9Y6Q6-2
	TNFRSF11A	ENST00000903844.1		c.590C>T	p.Ala197Val	missense	Exon 6 of 10	ENSP00000573903.1

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

GnomAD2 exomes AF: 0.545 AC: 136972 AN: 251466 AF XY: 0.531

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 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

African (AFR) AF: 0.643 AC: 21515 AN: 33448

American (AMR) AF: 0.664 AC: 29671 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 14224 AN: 26120

East Asian (EAS) AF: 0.687 AC: 27281 AN: 39686

South Asian (SAS) AF: 0.399 AC: 34427 AN: 86234

European-Finnish (FIN) AF: 0.532 AC: 28380 AN: 53382

Middle Eastern (MID) AF: 0.515 AC: 2968 AN: 5766

European-Non Finnish (NFE) AF: 0.507 AC: 563500 AN: 1110838

Other (OTH) AF: 0.528 AC: 31878 AN: 60344

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

African (AFR) AF: 0.640 AC: 26524 AN: 41468

American (AMR) AF: 0.626 AC: 9547 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1892 AN: 3472

East Asian (EAS) AF: 0.691 AC: 3577 AN: 5178

South Asian (SAS) AF: 0.412 AC: 1983 AN: 4818

European-Finnish (FIN) AF: 0.529 AC: 5576 AN: 10544

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34701 AN: 67950

Other (OTH) AF: 0.596 AC: 1249 AN: 2096

Alfa AF: 0.529 Hom.: 107962

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Bone Paget disease (1)
-	-	1	Disorder of bone (1)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0000059	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.39
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.083
MPC		1.1
ClinPred		0.0027	T
GERP RS		2.6
Varity_R		0.024
gMVP		0.75
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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