rs4764980

Variant names:

• chr12-100491329-G-A
• rs4764980
• NM_001206979.2:c.-189-1174G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206979.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.-189-1174G>A		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206977.2		c.-190+347G>A		intron	N/A	NP_001193906.1	F1DAL1
	NR1H4	NM_005123.4		c.-189-1174G>A		intron	N/A	NP_005114.1	Q96RI1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.-189-1174G>A		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000548884.5	TSL:1	c.-189-1174G>A		intron	N/A	ENSP00000448506.1	Q96RI1-2
	NR1H4	ENST00000549996.5	TSL:1	c.-189-1174G>A		intron	N/A	ENSP00000448978.1	Q96RI1-5

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

African (AFR) AF: 0.667 AC: 27510 AN: 41236

American (AMR) AF: 0.679 AC: 10321 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2095 AN: 3466

East Asian (EAS) AF: 0.903 AC: 4599 AN: 5092

South Asian (SAS) AF: 0.603 AC: 2883 AN: 4778

European-Finnish (FIN) AF: 0.409 AC: 4287 AN: 10472

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 33998 AN: 67860

Other (OTH) AF: 0.581 AC: 1218 AN: 2098

Alfa AF: 0.538 Hom.: 43468

Bravo AF: 0.603

Asia WGS AF: 0.711 AC: 2473 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4764980; hg19: chr12-100885107;