NM_003701.4:c.387+6634G>A

Variant names:

• chr13-42587927-G-A
• rs2148072
• NM_003701.4:c.387+6634G>A

Variant summary

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

The NM_003701.4(TNFSF11):​c.387+6634G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 152,052 control chromosomes in the GnomAD database, including 8,872 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 0.34 (8872 hom., cov: 32)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 15 publications found

Genes affected

TNFSF11 (HGNC:11926): (TNF superfamily member 11) This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]

TNFSF11 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003701.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	NM_003701.4	MANE Select	c.387+6634G>A		intron	N/A	NP_003692.1
	TNFSF11	NM_033012.4		c.168+6634G>A		intron	N/A	NP_143026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000398795.7	TSL:1 MANE Select	c.387+6634G>A		intron	N/A	ENSP00000381775.3
	TNFSF11	ENST00000358545.6	TSL:1	c.168+6634G>A		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50979 AN: 151934 Hom.: 8864 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.335 AC: 51008 AN: 152052 Hom.: 8872 Cov.: 32 AF XY: 0.335 AC XY: 24872 AN XY: 74332

African (AFR) AF: 0.276 AC: 11447 AN: 41460

American (AMR) AF: 0.281 AC: 4297 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3472

East Asian (EAS) AF: 0.217 AC: 1124 AN: 5182

South Asian (SAS) AF: 0.479 AC: 2305 AN: 4812

European-Finnish (FIN) AF: 0.344 AC: 3633 AN: 10556

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25241 AN: 67982

Other (OTH) AF: 0.361 AC: 760 AN: 2108

Alfa AF: 0.346 Hom.: 2821

Bravo AF: 0.323

Asia WGS AF: 0.355 AC: 1235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.50
PhyloP100		1.4
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: rs2148072; hg19: chr13-43162063;