rs61755050

chr12-100532530-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (22 hom.)
• Consequence: NR1H4 NM_001206979.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Benign. Variant got -12 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 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 291196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.518T>C	p.Met173Thr	missense_variant	5/11	ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.518T>C	p.Met173Thr	missense_variant	5/11	1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152212 Hom.: 3 Cov.: 33

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.: 2 AF XY: 0.00394 AC XY: 536 AN XY: 135910

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.: 22 Cov.: 31 AF XY: 0.00528 AC XY: 3843 AN XY: 727218

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.: 3 Cov.: 33 AF XY: 0.00311 AC XY: 232 AN XY: 74492

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.: 3

Bravo AF: 0.00336

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00386 AC: 469

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NR1H4: PP3, BS2 -

NR1H4-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;.;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
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	T
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

Other links and lift over

dbSNP: rs61755050; hg19: chr12-100926308;