12-100556593-G-T

Variant names:

• chr12-100556593-G-T
• rs35735
• NM_001206979.2:c.1079-5292G>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.1079-5292G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,890 control chromosomes in the GnomAD database, including 21,884 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 0.53 (21884 hom., cov: 32)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 9 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=-0.57).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 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.1079-5292G>T		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.1109-5292G>T		intron	N/A	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.1097-5292G>T		intron	N/A	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.1079-5292G>T		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.1109-5292G>T		intron	N/A	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.1097-5292G>T		intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80101 AN: 151770 Hom.: 21855 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.528 AC: 80181 AN: 151890 Hom.: 21884 Cov.: 32 AF XY: 0.519 AC XY: 38513 AN XY: 74232

African (AFR) AF: 0.474 AC: 19632 AN: 41418

American (AMR) AF: 0.463 AC: 7054 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1697 AN: 3468

East Asian (EAS) AF: 0.279 AC: 1447 AN: 5180

South Asian (SAS) AF: 0.343 AC: 1654 AN: 4816

European-Finnish (FIN) AF: 0.498 AC: 5245 AN: 10522

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.614 AC: 41687 AN: 67934

Other (OTH) AF: 0.521 AC: 1095 AN: 2102

Alfa AF: 0.572 Hom.: 69996

Bravo AF: 0.525

Asia WGS AF: 0.295 AC: 1031 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.5
DANN	Benign	0.91
PhyloP100		0.36
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: rs35735; hg19: chr12-100950371;