rs2229828

Positions:

• chr12-47857522-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000376.3(VDR):​c.444C>T​(p.Ser148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,158 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: VDR NM_000376.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.95

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-47857522-G-A is Benign according to our data. Variant chr12-47857522-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 791551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00584 (889/152282) while in subpopulation AFR AF= 0.0207 (859/41556). AF 95% confidence interval is 0.0195. There are 10 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.444C>T	p.Ser148=	synonymous_variant	5/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.444C>T	p.Ser148=	synonymous_variant	5/10	1	NM_000376.3	ENSP00000449573	P1

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 884 AN: 152164 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00163 AC: 408 AN: 249982 Hom.: 4 AF XY: 0.00123 AC XY: 167 AN XY: 135282

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000691 AC: 1010 AN: 1461876 Hom.: 11 Cov.: 32 AF XY: 0.000582 AC XY: 423 AN XY: 727244

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00584 AC: 889 AN: 152282 Hom.: 10 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74462

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00696

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Vitamin D-dependent rickets type II with alopecia 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). No publications were found based on this search. Allele frequency data from public databases allowed determination 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
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.97
DANN	Benign	0.87

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: rs2229828; hg19: chr12-48251305; COSMIC: COSV99969078; COSMIC: COSV99969078;