chr13-42607866-G-T

Variant names:

• chr13-42607866-G-T
• rs1054016
• NM_003701.4:c.*948G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003701.4(TNFSF11):​c.*948G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,648 control chromosomes in the GnomAD database, including 10,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10309 hom., cov: 32)
  • Exomes 𝑓: 0.41 (25 hom.)
• Consequence: TNFSF11 NM_003701.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600
• Publications: 31 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: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, PanelApp Australia
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 13-42607866-G-T is Benign according to our data. Variant chr13-42607866-G-T is described in ClinVar as Benign. ClinVar VariationId is 312251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 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.*948G>T		3_prime_UTR	Exon 5 of 5	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.*948G>T		3_prime_UTR	Exon 7 of 7	NP_143026.1	O14788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000398795.7	TSL:1 MANE Select	c.*948G>T		3_prime_UTR	Exon 5 of 5	ENSP00000381775.3	O14788-1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53521 AN: 151008 Hom.: 10311 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.413 AC: 217 AN: 526 Hom.: 25 Cov.: 0 AF XY: 0.432 AC XY: 134 AN XY: 310

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.393 AC: 48 AN: 122

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.420 AC: 167 AN: 398

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.354 AC: 53522 AN: 151122 Hom.: 10309 Cov.: 32 AF XY: 0.358 AC XY: 26436 AN XY: 73802

African (AFR) AF: 0.194 AC: 8025 AN: 41380

American (AMR) AF: 0.360 AC: 5459 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1060 AN: 3468

East Asian (EAS) AF: 0.454 AC: 2343 AN: 5156

South Asian (SAS) AF: 0.328 AC: 1573 AN: 4800

European-Finnish (FIN) AF: 0.488 AC: 4975 AN: 10192

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.426 AC: 28824 AN: 67652

Other (OTH) AF: 0.359 AC: 753 AN: 2098

Alfa AF: 0.0794 Hom.: 195

Bravo AF: 0.341

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive osteopetrosis 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		0.0060
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: rs1054016; hg19: chr13-43182002;