rs2073617

Variant names:

• chr8-118952044-G-A
• rs2073617
• NM_002546.4:c.-223C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-118952044-G-A
• chr8-118952044-G-T

Variant summary

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

The NM_002546.4(TNFRSF11B):​c.-223C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 564,500 control chromosomes in the GnomAD database, including 86,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26027 hom., cov: 30)
  • Exomes 𝑓: 0.55 (60827 hom.)
• Consequence: TNFRSF11B NM_002546.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0960
• Publications: 141 publications found

Genes affected

TNFRSF11B (HGNC:11909): (TNF receptor superfamily member 11b) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

COLEC10 (HGNC:2220): (collectin subfamily member 10) This gene encodes a member of the C-lectin family, proteins that possess collagen-like sequences and carbohydrate recognition domains. The other members of this family are secreted proteins and bind to carbohydrate antigens on microorganisms facilitating their recognition and removal. This gene product is a cytosolic protein, a characteristic that suggests that it may have different biological functions than other C-lectins. [provided by RefSeq, Jul 2008]

COLEC10 Gene-Disease associations (from GenCC):

• 3MC syndrome 3

  Inheritance: AR Classification: STRONG Submitted by: G2P
• 3MC syndrome

  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=-0.81).
• BP6: Variant 8-118952044-G-A is Benign according to our data. Variant chr8-118952044-G-A is described in ClinVar as Benign. ClinVar VariationId is 361702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11B	NM_002546.4	c.-223C>T		upstream_gene_variant		ENST00000297350.9	NP_002537.3
COLEC10	NM_001324095.2	c.-658G>A		upstream_gene_variant			NP_001311024.1
COLEC10	XM_005250756.4	c.-394G>A		upstream_gene_variant			XP_005250813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF11B	ENST00000297350.9	c.-223C>T		upstream_gene_variant		1	NM_002546.4	ENSP00000297350.4
TNFRSF11B	ENST00000517352.1	n.-223C>T		upstream_gene_variant		1		ENSP00000427924.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87020 AN: 151602 Hom.: 25975 Cov.: 30

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.591

GnomAD4 exome AF: 0.545 AC: 225020 AN: 412778 Hom.: 60827 Cov.: 3 AF XY: 0.548 AC XY: 119869 AN XY: 218606

African (AFR) AF: 0.760 AC: 8824 AN: 11608

American (AMR) AF: 0.426 AC: 8068 AN: 18954

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 8129 AN: 12702

East Asian (EAS) AF: 0.623 AC: 17537 AN: 28148

South Asian (SAS) AF: 0.621 AC: 27832 AN: 44794

European-Finnish (FIN) AF: 0.543 AC: 13527 AN: 24926

Middle Eastern (MID) AF: 0.653 AC: 1873 AN: 2868

European-Non Finnish (NFE) AF: 0.512 AC: 125542 AN: 245204

Other (OTH) AF: 0.581 AC: 13688 AN: 23574

GnomAD4 genome AF: 0.574 AC: 87120 AN: 151722 Hom.: 26027 Cov.: 30 AF XY: 0.577 AC XY: 42750 AN XY: 74136

African (AFR) AF: 0.745 AC: 30844 AN: 41396

American (AMR) AF: 0.486 AC: 7418 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2101 AN: 3466

East Asian (EAS) AF: 0.619 AC: 3159 AN: 5102

South Asian (SAS) AF: 0.631 AC: 3026 AN: 4796

European-Finnish (FIN) AF: 0.518 AC: 5449 AN: 10516

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.491 AC: 33363 AN: 67890

Other (OTH) AF: 0.597 AC: 1252 AN: 2098

Alfa AF: 0.557 Hom.: 11682

Bravo AF: 0.573

Asia WGS AF: 0.686 AC: 2386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12054556, 18938269, 21994215, 22965192, 19661483, 16678184) -

Hyperphosphatasemia with bone disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.79
PhyloP100		-0.096
PromoterAI		-0.024	Neutral
Mutation Taster		=300/0	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: rs2073617; hg19: chr8-119964283;