chr12-100532530-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_001206979.2(NR1H4):c.518T>C(p.Met173Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,614,144 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 22 hom. )

Consequence

NR1H4
NM_001206979.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 7.66

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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015372664).

BP6

Variant 12-100532530-T-C is Benign according to our data. Variant chr12-100532530-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 291196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-100532530-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00364 (555/152330) while in subpopulation NFE AF= 0.00645 (439/68028). AF 95% confidence interval is 0.00595. There are 3 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2 link	c.518T>C	p.Met173Thr	missense_variant	Exon 5 of 11	ENST00000392986.8	NP_001193908.1	Q96RI1-1F1DAL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8 link	c.518T>C	p.Met173Thr	missense_variant	Exon 5 of 11	1	NM_001206979.2	ENSP00000376712.3		Q96RI1-1

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00645

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00380

AC:

956

AN:

251478

Hom.:

AF XY:

0.00394

AC XY:

536

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00629

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00535

AC:

7818

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

3843

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00288

Gnomad4 FIN exome

AF:

0.00352

Gnomad4 NFE exome

AF:

0.00630

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00364

AC:

555

AN:

152330

Hom.:

Cov.:

AF XY:

0.00311

AC XY:

232

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00645

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00551

Hom.:

Bravo

AF:

0.00336

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00386

AC:

469

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00516

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NR1H4: PP3, BS2 -

NR1H4-related disorder

Uncertain:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NR1H4 c.518T>C variant is predicted to result in the amino acid substitution p.Met173Thr. This variant has been reported to be associated with intrahepatic cholestasis of pregnancy (Van Mil et al. 2007. PubMed ID: 17681172). This variant is reported in 0.64% of alleles in individuals of European (Non-Finnish) descent in gnomAD including two homozygotes of unknown phenotype, which might be too common to be a highly penetrant cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Sep 13, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;.;.;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

T;.;T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.015

T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.040

.;.;.;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

D;D;.;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.049

D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;.;D;D

Polyphen

0.99

.;.;.;D;D

Vest4

0.90

MVP

0.98

MPC

1.1

ClinPred

0.017

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.64

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