rs4764980

Positions:

• chr12-100491329-G-A
• chr12-100491329-G-C
• chr12-100491329-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206979.2(NR1H4):​c.-189-1174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,412 control chromosomes in the GnomAD database, including 26,091 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (26091 hom., cov: 29)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.-189-1174G>A		intron_variant		ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.-189-1174G>A		intron_variant		1	NM_001206979.2	ENSP00000376712	A1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87339 AN: 151296 Hom.: 26051 Cov.: 29

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.903

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.587

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.577 AC: 87432 AN: 151412 Hom.: 26091 Cov.: 29 AF XY: 0.577 AC XY: 42671 AN XY: 73904

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.604

Gnomad4 EAS AF: 0.903

Gnomad4 SAS AF: 0.603

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.581

Alfa AF: 0.527 Hom.: 30218

Bravo AF: 0.603

Asia WGS AF: 0.711 AC: 2473 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	12
DANN	Benign	0.53

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: rs4764980; hg19: chr12-100885107;