NM_003839.4:c.283+1036A>T

Variant names:

• chr18-62350973-A-T
• rs11664594
• NM_003839.4:c.283+1036A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003839.4(TNFRSF11A):​c.283+1036A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 147,294 control chromosomes in the GnomAD database, including 30,033 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (30033 hom., cov: 26)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	NM_003839.4	MANE Select	c.283+1036A>T		intron	N/A	NP_003830.1
	TNFRSF11A	NM_001278268.2		c.283+1036A>T		intron	N/A	NP_001265197.1
	TNFRSF11A	NM_001270950.2		c.283+1036A>T		intron	N/A	NP_001257879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF11A	ENST00000586569.3	TSL:1 MANE Select	c.283+1036A>T		intron	N/A	ENSP00000465500.1
	TNFRSF11A	ENST00000269485.11	TSL:1	c.283+1036A>T		intron	N/A	ENSP00000269485.7
	TNFRSF11A	ENST00000903844.1		c.283+1036A>T		intron	N/A	ENSP00000573903.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 94499 AN: 147190 Hom.: 29985 Cov.: 26

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.493

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.627

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

GnomAD4 genome AF: 0.642 AC: 94603 AN: 147294 Hom.: 30033 Cov.: 26 AF XY: 0.644 AC XY: 46126 AN XY: 71588

African (AFR) AF: 0.662 AC: 26524 AN: 40046

American (AMR) AF: 0.628 AC: 9313 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2054 AN: 3410

East Asian (EAS) AF: 0.598 AC: 2989 AN: 4998

South Asian (SAS) AF: 0.605 AC: 2804 AN: 4634

European-Finnish (FIN) AF: 0.708 AC: 6635 AN: 9366

Middle Eastern (MID) AF: 0.496 AC: 137 AN: 276

European-Non Finnish (NFE) AF: 0.632 AC: 42205 AN: 66778

Other (OTH) AF: 0.625 AC: 1290 AN: 2064

Alfa AF: 0.648 Hom.: 4031

Bravo AF: 0.630

Asia WGS AF: 0.624 AC: 2163 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-1.1
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: rs11664594; hg19: chr18-60018206;