12-100498752-T-G

Variant names:

• chr12-100498752-T-G
• rs7968366
• NM_001206979.2:c.79+5350T>G

Variant summary

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

The NM_001206979.2(NR1H4):​c.79+5350T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,148 control chromosomes in the GnomAD database, including 5,354 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 0.18 (5354 hom., cov: 32)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694
• Publications: 0 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 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.79+5350T>G		intron	N/A	NP_001193908.1
	NR1H4	NM_001206977.2		c.79+5350T>G		intron	N/A	NP_001193906.1
	NR1H4	NM_005123.4		c.79+5350T>G		intron	N/A	NP_005114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.79+5350T>G		intron	N/A	ENSP00000376712.3
	NR1H4	ENST00000548884.5	TSL:1	c.79+5350T>G		intron	N/A	ENSP00000448506.1
	NR1H4	ENST00000549996.5	TSL:1	c.79+5350T>G		intron	N/A	ENSP00000448978.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27373 AN: 152030 Hom.: 5326 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.180 AC: 27437 AN: 152148 Hom.: 5354 Cov.: 32 AF XY: 0.182 AC XY: 13507 AN XY: 74394

African (AFR) AF: 0.461 AC: 19126 AN: 41446

American (AMR) AF: 0.147 AC: 2240 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3470

East Asian (EAS) AF: 0.454 AC: 2346 AN: 5172

South Asian (SAS) AF: 0.144 AC: 692 AN: 4812

European-Finnish (FIN) AF: 0.0465 AC: 494 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1925 AN: 68016

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.0426 Hom.: 102

Bravo AF: 0.204

Asia WGS AF: 0.310 AC: 1077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.059
DANN	Benign	0.36
PhyloP100		-0.69
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: rs7968366; hg19: chr12-100892530;