rs760186422

Variant names:

• chr12-100503505-C-G
• rs760186422
• NM_001206979.2:c.80-7273C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001206979.2(NR1H4):​c.80-7273C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,588,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.142
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-100503505-C-G is Benign according to our data. Variant chr12-100503505-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3036230.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000131 (20/152172) while in subpopulation AFR AF = 0.000483 (20/41450). AF 95% confidence interval is 0.00032. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.80-7273C>G		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.109+9C>G		intron	N/A	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.109+9C>G		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.80-7273C>G		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.109+9C>G		intron	N/A	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.109+9C>G		intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000138 AC: 3 AN: 218094 AF XY: 0.0000166

Gnomad AFR exome AF: 0.000224

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000836 AC: 12 AN: 1436222 Hom.: 0 Cov.: 30 AF XY: 0.00000980 AC XY: 7 AN XY: 713952

African (AFR) AF: 0.000330 AC: 11 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 43824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 83896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106850

Other (OTH) AF: 0.00 AC: 0 AN: 59902

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74348

African (AFR) AF: 0.000483 AC: 20 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NR1H4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		-0.14
PromoterAI		-0.034	Neutral

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: rs760186422; hg19: chr12-100897283;