Variant 12-100505623-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001206979.2(NR1H4):c.80-5155C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 701,566 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

NR1H4
NM_001206979.2 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.215

Variant links:

Genes affected

NR1H4 (HGNC:7967): (nuclear receptor subfamily 1 group H member 4) This gene encodes a ligand-activated transcription factor that shares structural features in common with nuclear hormone receptor family members. This protein functions as a receptor for bile acids, and when bound to bile acids, binds to DNA and regulates the expression of genes involved in bile acid synthesis and transport. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]

NR1H4 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=0.008201271).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00185 (282/152284) while in subpopulation NFE AF= 0.00321 (218/68016). AF 95% confidence interval is 0.00286. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2 linkuse as main transcript	c.80-5155C>G		intron_variant		ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8 linkuse as main transcript	c.80-5155C>G		intron_variant		1	NM_001206979.2	A1	Q96RI1-1

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00320

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00145

AC:

185

AN:

127758

Hom.:

AF XY:

0.00137

AC XY:

AN XY:

69962

show subpopulations

Gnomad AFR exome

AF:

0.000822

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000403

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00198

AC:

1087

AN:

549282

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

530

AN XY:

297370

show subpopulations

Gnomad4 AFR exome

AF:

0.000507

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000399

Gnomad4 FIN exome

AF:

0.00157

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152284

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00321

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000647

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000887

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.2

DANN

Benign

0.23

Eigen

Benign

-0.79

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.12

.;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

-1.8

.;N

REVEL

Benign

0.082

Sift

Uncertain

0.025

.;D

Sift4G

Benign

0.15

.;T

Vest4

0.051

MutPred

0.15

Gain of catalytic residue at H40 (P = 0.0158);Gain of catalytic residue at H40 (P = 0.0158);

MVP

0.16

ClinPred

0.0028

GERP RS

-1.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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