NM_003839.4:c.428-1416T>A

Variant names:

• chr18-62356832-T-A
• rs11665260
• NM_003839.4:c.428-1416T>A

Variant summary

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

The NM_003839.4(TNFRSF11A):​c.428-1416T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,146 control chromosomes in the GnomAD database, including 3,773 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 0.19 (3773 hom., cov: 32)
• Consequence: TNFRSF11A NM_003839.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.822
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4	c.428-1416T>A		intron_variant	Intron 4 of 9	ENST00000586569.3	NP_003830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11A	ENST00000586569.3	c.428-1416T>A		intron_variant	Intron 4 of 9	1	NM_003839.4	ENSP00000465500.1
TNFRSF11A	ENST00000269485.11	c.428-1416T>A		intron_variant	Intron 4 of 6	1		ENSP00000269485.7

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29382 AN: 152028 Hom.: 3773 Cov.: 32

Gnomad AFR AF: 0.0630

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.193 AC: 29382 AN: 152146 Hom.: 3773 Cov.: 32 AF XY: 0.196 AC XY: 14553 AN XY: 74360

African (AFR) AF: 0.0628 AC: 2610 AN: 41540

American (AMR) AF: 0.142 AC: 2165 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3468

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5184

South Asian (SAS) AF: 0.236 AC: 1136 AN: 4814

European-Finnish (FIN) AF: 0.341 AC: 3604 AN: 10562

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18297 AN: 67974

Other (OTH) AF: 0.165 AC: 348 AN: 2110

Alfa AF: 0.232 Hom.: 626

Bravo AF: 0.169

Asia WGS AF: 0.107 AC: 370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.28
PhyloP100		-0.82
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: rs11665260; hg19: chr18-60024065;