rs17030285

Variant names:

• chr12-100536435-C-A
• rs17030285
• NM_001206979.2:c.733-77C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-100536435-C-A
• chr12-100536435-C-G
• chr12-100536435-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001206979.2(NR1H4):​c.733-77C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 826,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 11 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.733-77C>A		intron	N/A	NP_001193908.1
	NR1H4	NM_001206993.2		c.763-77C>A		intron	N/A	NP_001193922.1
	NR1H4	NM_001206992.2		c.751-77C>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.733-77C>A		intron	N/A	ENSP00000376712.3
	NR1H4	ENST00000551379.5	TSL:1	c.763-77C>A		intron	N/A	ENSP00000447149.1
	NR1H4	ENST00000188403.7	TSL:1	c.751-77C>A		intron	N/A	ENSP00000188403.7

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151406 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000888 AC: 6 AN: 675562 Hom.: 0 AF XY: 0.0000138 AC XY: 5 AN XY: 363438

African (AFR) AF: 0.00 AC: 0 AN: 17976

American (AMR) AF: 0.00 AC: 0 AN: 40692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20504

East Asian (EAS) AF: 0.00 AC: 0 AN: 35896

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4206

European-Non Finnish (NFE) AF: 0.0000124 AC: 5 AN: 403230

Other (OTH) AF: 0.00 AC: 0 AN: 34254

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151406 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73868

African (AFR) AF: 0.0000243 AC: 1 AN: 41194

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67860

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 72

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.70
DANN	Benign	0.41
PhyloP100		-0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17030285; hg19: chr12-100930213;