rs121908656

Variant names:

• chr18-62359956-T-C
• rs121908656
• NM_003839.4:c.523T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_003839.4(TNFRSF11A):​c.523T>C​(p.Cys175Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNFRSF11A NM_003839.4 missense, splice_region
• Scores: Splicing: ADA: 0.4023
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.95

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 18-62359956-T-C is Pathogenic according to our data. Variant chr18-62359956-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6302.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.523T>C	p.Cys175Arg	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.523T>C	p.Cys175Arg	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.523T>C	p.Cys175Arg	missense_variant, splice_region_variant	Exon 6 of 7	1		ENSP00000269485.7
TNFRSF11A	ENST00000587697.1	n.441T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461454 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive osteopetrosis 7 Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;T;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.9	.;H;H;H;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	.;D;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;D;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.96, 0.88, 0.97, 0.97
MVP		0.96
MPC		3.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.40
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

Publications

LitVar

Other links and lift over

dbSNP: rs121908656; hg19: chr18-60027189;