rs3826619

Variant names:

• chr18-62348517-G-A
• rs3826619
• NM_003839.4:c.157+268G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-62348517-G-A
• chr18-62348517-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003839.4(TNFRSF11A):​c.157+268G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,144 control chromosomes in the GnomAD database, including 1,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.10 (1146 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0810
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive osteopetrosis 7

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

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

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

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-62348517-G-A is Benign according to our data. Variant chr18-62348517-G-A is described in ClinVar as Benign. ClinVar VariationId is 1263481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.157+268G>A		intron_variant	Intron 2 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.157+268G>A		intron_variant	Intron 2 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.157+268G>A		intron_variant	Intron 2 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15732 AN: 152026 Hom.: 1145 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.120

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.103 AC: 15740 AN: 152144 Hom.: 1146 Cov.: 32 AF XY: 0.111 AC XY: 8246 AN XY: 74368

African (AFR) AF: 0.0252 AC: 1045 AN: 41512

American (AMR) AF: 0.131 AC: 2001 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3468

East Asian (EAS) AF: 0.305 AC: 1579 AN: 5178

South Asian (SAS) AF: 0.176 AC: 849 AN: 4814

European-Finnish (FIN) AF: 0.192 AC: 2025 AN: 10552

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7462 AN: 68000

Other (OTH) AF: 0.119 AC: 251 AN: 2114

Alfa AF: 0.107 Hom.: 1440

Bravo AF: 0.0938

Asia WGS AF: 0.237 AC: 821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.41
PhyloP100		0.081
Mutation Taster		=100/0	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: rs3826619; hg19: chr18-60015750;