13-42574240-C-T

Variant names:

• chr13-42574240-C-T
• rs886050251
• NM_003701.4:c.-64C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003701.4(TNFSF11):​c.-64C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNFSF11 NM_003701.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.02
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	ENST00000398795.7	NP_003692.1
TNFSF11	NM_003701.4	c.-64C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000398795.7	NP_003692.1
TNFSF11	NM_033012.4	c.-1+2502C>T		intron_variant	Intron 3 of 6		NP_143026.1
TNFSF11	XM_047430707.1	c.-1+2502C>T		intron_variant	Intron 1 of 4		XP_047286663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000398795.7	c.-64C>T		5_prime_UTR_variant	Exon 1 of 5	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6	c.-1+2502C>T		intron_variant	Intron 3 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.25e-7 AC: 1 AN: 1379702 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681166

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31008

American (AMR) AF: 0.00 AC: 0 AN: 35546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24906

East Asian (EAS) AF: 0.00 AC: 0 AN: 35446

South Asian (SAS) AF: 0.00 AC: 0 AN: 78462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1066748

Other (OTH) AF: 0.00 AC: 0 AN: 57144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.96
PhyloP100		-3.0
PromoterAI		0.039	Neutral

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: rs886050251; hg19: chr13-43148376;