rs138818878

chr13-42574410-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003701.4(TNFSF11):c.107C>G(p.Pro36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,570,004 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 34)
  • Exomes 𝑓: 0.028 (690 hom.)
• Consequence: TNFSF11 NM_003701.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021615326).
• BP6: Variant 13-42574410-C-G is Benign according to our data. Variant chr13-42574410-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 312229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.021 (3191/152264) while in subpopulation NFE AF= 0.0318 (2161/68014). AF 95% confidence interval is 0.0307. There are 54 homozygotes in gnomad4. There are 1559 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF11	NM_003701.4	c.107C>G	p.Pro36Arg	missense_variant	1/5	ENST00000398795.7
TNFSF11	NM_033012.4	c.-1+2672C>G		intron_variant
TNFSF11	XM_047430707.1	c.-1+2672C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF11	ENST00000398795.7	c.107C>G	p.Pro36Arg	missense_variant	1/5	1	NM_003701.4	P1
TNFSF11	ENST00000358545.6	c.-1+2672C>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3193 AN: 152152 Hom.: 54 Cov.: 34

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0460

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0197 AC: 3482 AN: 177200 Hom.: 62 AF XY: 0.0195 AC XY: 1899 AN XY: 97212

Gnomad AFR exome AF: 0.00513

Gnomad AMR exome AF: 0.00854

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0281 AC: 39808 AN: 1417740 Hom.: 690 Cov.: 33 AF XY: 0.0276 AC XY: 19342 AN XY: 701592

Gnomad4 AFR exome AF: 0.00494

Gnomad4 AMR exome AF: 0.00882

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0429

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0210 AC: 3191 AN: 152264 Hom.: 54 Cov.: 34 AF XY: 0.0209 AC XY: 1559 AN XY: 74444

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0460

Gnomad4 NFE AF: 0.0318

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0264 Hom.: 16

Bravo AF: 0.0169

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0311 AC: 120

ESP6500AA AF: 0.00618 AC: 22

ESP6500EA AF: 0.0245 AC: 178

ExAC AF: 0.0144 AC: 1641

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 10, 2021

- -

Increased bone mineral density Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 19, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal recessive osteopetrosis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0022	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.79	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.018	D
Polyphen		0.74	P
Vest4		0.083
ClinPred		0.013	T
GERP RS		3.8
Varity_R		0.049
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs138818878; hg19: chr13-43148546; COSMIC: COSV53477660;