NM_003701.4:c.107C>G

Variant names:

• chr13-42574410-C-G
• rs138818878
• NM_003701.4:c.107C>G

Variant summary

Our verdict is Benign. The variant received -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. 11/18 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:5
• Conservation: PhyloP100: 1.50
• Publications: 8 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 (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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

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.107C>G	p.Pro36Arg	missense	Exon 1 of 5	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.-1+2672C>G		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.107C>G	p.Pro36Arg	missense	Exon 1 of 5	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.-1+2672C>G		intron	N/A	ENSP00000351347.2	O14788-2

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

GnomAD2 exomes AF: 0.0197 AC: 3482 AN: 177200 AF XY: 0.0195

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 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

African (AFR) AF: 0.00494 AC: 161 AN: 32618

American (AMR) AF: 0.00882 AC: 348 AN: 39440

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 234 AN: 25370

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37906

South Asian (SAS) AF: 0.0122 AC: 997 AN: 81400

European-Finnish (FIN) AF: 0.0429 AC: 1983 AN: 46192

Middle Eastern (MID) AF: 0.00557 AC: 23 AN: 4130

European-Non Finnish (NFE) AF: 0.0318 AC: 34691 AN: 1092044

Other (OTH) AF: 0.0234 AC: 1370 AN: 58640

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

African (AFR) AF: 0.00496 AC: 206 AN: 41552

American (AMR) AF: 0.0118 AC: 181 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.0460 AC: 488 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0318 AC: 2161 AN: 68014

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive osteopetrosis 2 (1)
-	-	1	Increased bone mineral density (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.5
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
PromoterAI		-0.075	Neutral
Varity_R		0.049
gMVP		0.27
Mutation Taster		=292/8	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: rs138818878; hg19: chr13-43148546; COSMIC: COSV53477660;