12-100481123-C-T

Variant names:

• chr12-100481123-C-T
• rs11110390
• NM_001206979.2:c.-190+7064C>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.-190+7064C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 151,984 control chromosomes in the GnomAD database, including 5,689 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 0.24 (5689 hom., cov: 32)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.974
• 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 (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.-190+7064C>T		intron_variant	Intron 1 of 10	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.-190+7064C>T		intron_variant	Intron 1 of 10	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36949 AN: 151866 Hom.: 5692 Cov.: 32

Gnomad AFR AF: 0.0697

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.243 AC: 36945 AN: 151984 Hom.: 5689 Cov.: 32 AF XY: 0.247 AC XY: 18317 AN XY: 74264

African (AFR) AF: 0.0695 AC: 2882 AN: 41460

American (AMR) AF: 0.213 AC: 3261 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3470

East Asian (EAS) AF: 0.0540 AC: 280 AN: 5182

South Asian (SAS) AF: 0.308 AC: 1483 AN: 4818

European-Finnish (FIN) AF: 0.433 AC: 4547 AN: 10512

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22409 AN: 67956

Other (OTH) AF: 0.262 AC: 553 AN: 2108

Alfa AF: 0.290 Hom.: 12759

Bravo AF: 0.217

Asia WGS AF: 0.188 AC: 653 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	0.66
DANN	Benign	0.66
PhyloP100		-0.97
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: rs11110390; hg19: chr12-100874901;