rs11574115

Positions:

chr12-47844945-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000376.3(VDR):c.1085C>T(p.Thr362Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,050 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

VDR
NM_000376.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011026263).

BP6

Variant 12-47844945-G-A is Benign according to our data. Variant chr12-47844945-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 754732.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3 linkuse as main transcript	c.1085C>T	p.Thr362Ile	missense_variant	10/10	ENST00000549336.6	NP_000367.1	P11473-1F1D8P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6 linkuse as main transcript	c.1085C>T	p.Thr362Ile	missense_variant	10/10	1	NM_000376.3	ENSP00000449573.2		P11473-1

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00546

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000378

AC:

AN:

251378

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00560

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

204

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152242

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00544

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000453

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 16, 2023

Variant summary: VDR c.1085C>T (p.Thr362Ile) results in a non-conservative amino acid change located in the nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251378 control chromosomes, predominantly at a frequency of 0.0056 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes, suggesting it could be a benign polymorphism found primarily in individuals of African ancestry. To our knowledge, no occurrence of c.1085C>T in individuals affected with Vitamin D-Dependent Rickets Type II With Alopecia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Vitamin D-dependent rickets type II with alopecia

Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;D;D;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

.;.;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.46

N;N;N;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Benign

0.24

Sift

Benign

0.031

D;D;D;T

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.044

B;B;B;.

Vest4

0.11

MVP

0.90

MPC

0.47

ClinPred

0.064

GERP RS

3.1

Varity_R

0.40

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over