rs1805034

Positions:

• chr18-62360008-C-A
• chr18-62360008-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003839.4(TNFRSF11A):​c.575C>A​(p.Ala192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A192V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF11A NM_003839.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31532103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.575C>A	p.Ala192Glu	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	c.575C>A	p.Ala192Glu	missense_variant	6/10	1	NM_003839.4	ENSP00000465500	P2
TNFRSF11A	ENST00000269485.11	c.575C>A	p.Ala192Glu	missense_variant	6/7	1		ENSP00000269485	A2
TNFRSF11A	ENST00000587697.1	n.493C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;.;.;.;D
Eigen	Benign	0.041
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.60	T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	.;M;M;M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	.;D;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.018	.;D;.;.;.
Sift4G	Uncertain	0.026	.;D;D;D;D
Polyphen		0.99	.;.;.;.;D
Vest4		0.23, 0.17, 0.20, 0.27
MutPred		0.36		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.70
MPC		1.7
ClinPred		0.90	D
GERP RS		2.6
Varity_R		0.55
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1805034; hg19: chr18-60027241;