12-100550170-G-A

Variant names:

• chr12-100550170-G-A
• rs10860603
• NM_001206979.2:c.1078+9352G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206979.2(NR1H4):​c.1078+9352G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,002 control chromosomes in the GnomAD database, including 4,337 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 0.20 (4337 hom., cov: 32)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.1078+9352G>A		intron	N/A	NP_001193908.1
	NR1H4	NM_001206993.2		c.1108+9352G>A		intron	N/A	NP_001193922.1
	NR1H4	NM_001206992.2		c.1096+9352G>A		intron	N/A	NP_001193921.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.1078+9352G>A		intron	N/A	ENSP00000376712.3
	NR1H4	ENST00000551379.5	TSL:1	c.1108+9352G>A		intron	N/A	ENSP00000447149.1
	NR1H4	ENST00000188403.7	TSL:1	c.1096+9352G>A		intron	N/A	ENSP00000188403.7

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30032 AN: 151882 Hom.: 4325 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.198 AC: 30060 AN: 152002 Hom.: 4337 Cov.: 32 AF XY: 0.210 AC XY: 15629 AN XY: 74296

African (AFR) AF: 0.154 AC: 6373 AN: 41468

American (AMR) AF: 0.393 AC: 5993 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3470

East Asian (EAS) AF: 0.716 AC: 3696 AN: 5162

South Asian (SAS) AF: 0.287 AC: 1380 AN: 4816

European-Finnish (FIN) AF: 0.201 AC: 2121 AN: 10544

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9509 AN: 67962

Other (OTH) AF: 0.217 AC: 458 AN: 2110

Alfa AF: 0.166 Hom.: 2609

Bravo AF: 0.212

Asia WGS AF: 0.447 AC: 1548 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.27
DANN	Benign	0.62
PhyloP100		-0.15
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: rs10860603; hg19: chr12-100943948;