rs2277438

Variant names:

• chr13-42581032-G-A
• rs2277438
• NM_003701.4:c.220-94G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-42581032-G-A
• chr13-42581032-G-C

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.220-94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,337,336 control chromosomes in the GnomAD database, including 449,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49688 hom., cov: 32)
  • Exomes 𝑓: 0.82 (400205 hom.)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.40
• Publications: 58 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=-0.91).
• BP6: Variant 13-42581032-G-A is Benign according to our data. Variant chr13-42581032-G-A is described in ClinVar as Benign. ClinVar VariationId is 1183681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.86 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.220-94G>A		intron	N/A	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.1-94G>A		intron	N/A	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.220-94G>A		intron	N/A	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.1-94G>A		intron	N/A	ENSP00000351347.2	O14788-2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122660 AN: 152076 Hom.: 49654 Cov.: 32

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.808

GnomAD4 exome AF: 0.820 AC: 971627 AN: 1185142 Hom.: 400205 AF XY: 0.824 AC XY: 496768 AN XY: 603196

African (AFR) AF: 0.806 AC: 22280 AN: 27626

American (AMR) AF: 0.628 AC: 27442 AN: 43706

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 20030 AN: 24392

East Asian (EAS) AF: 0.672 AC: 25609 AN: 38124

South Asian (SAS) AF: 0.884 AC: 70175 AN: 79360

European-Finnish (FIN) AF: 0.869 AC: 45237 AN: 52034

Middle Eastern (MID) AF: 0.856 AC: 3667 AN: 4284

European-Non Finnish (NFE) AF: 0.828 AC: 715277 AN: 864382

Other (OTH) AF: 0.818 AC: 41910 AN: 51234

GnomAD4 genome AF: 0.806 AC: 122742 AN: 152194 Hom.: 49688 Cov.: 32 AF XY: 0.808 AC XY: 60118 AN XY: 74402

African (AFR) AF: 0.802 AC: 33302 AN: 41506

American (AMR) AF: 0.694 AC: 10610 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2836 AN: 3470

East Asian (EAS) AF: 0.704 AC: 3640 AN: 5174

South Asian (SAS) AF: 0.882 AC: 4264 AN: 4834

European-Finnish (FIN) AF: 0.865 AC: 9158 AN: 10590

Middle Eastern (MID) AF: 0.870 AC: 254 AN: 292

European-Non Finnish (NFE) AF: 0.827 AC: 56235 AN: 68006

Other (OTH) AF: 0.810 AC: 1712 AN: 2114

Alfa AF: 0.815 Hom.: 65249

Bravo AF: 0.788

Asia WGS AF: 0.791 AC: 2749 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.9
DANN	Benign	0.52
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2277438; hg19: chr13-43155168; COSMIC: COSV53476884;