chr12-47846444-G-A

Variant names:

• chr12-47846444-G-A
• rs121909798
• NM_000376.3:c.915C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000376.3(VDR):​c.915C>T​(p.His305His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VDR NM_000376.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.04
• Publications: 20 publications found

Genes affected

VDR (HGNC:12679): (vitamin D receptor) This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

VDR Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-47846444-G-A is Benign according to our data. Variant chr12-47846444-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3671764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.04 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.915C>T	p.His305His	synonymous_variant	Exon 9 of 10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.915C>T	p.His305His	synonymous_variant	Exon 9 of 10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411390 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 697410

African (AFR) AF: 0.00 AC: 0 AN: 32186

American (AMR) AF: 0.00 AC: 0 AN: 36944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25294

East Asian (EAS) AF: 0.00 AC: 0 AN: 36826

South Asian (SAS) AF: 0.00 AC: 0 AN: 80336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085952

Other (OTH) AF: 0.00 AC: 0 AN: 58564

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.7
DANN	Benign	0.52
PhyloP100		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121909798; hg19: chr12-48240227;