12-100536435-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206979.2(NR1H4):​c.733-77C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 826,604 control chromosomes in the GnomAD database, including 13,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1820 hom., cov: 32)
  • Exomes 𝑓: 0.17 (11882 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-100536435-C-G is Benign according to our data. Variant chr12-100536435-C-G is described in ClinVar as Benign. ClinVar VariationId is 1231661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.281 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.733-77C>G		intron	N/A	NP_001193908.1
	NR1H4	NM_001206993.2		c.763-77C>G		intron	N/A	NP_001193922.1
	NR1H4	NM_001206992.2		c.751-77C>G		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>G		intron	N/A	ENSP00000376712.3
	NR1H4	ENST00000551379.5	TSL:1	c.763-77C>G		intron	N/A	ENSP00000447149.1
	NR1H4	ENST00000188403.7	TSL:1	c.751-77C>G		intron	N/A	ENSP00000188403.7

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19700 AN: 151350 Hom.: 1808 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.0955

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.167 AC: 112624 AN: 675138 Hom.: 11882 AF XY: 0.167 AC XY: 60840 AN XY: 363238

African (AFR) AF: 0.0280 AC: 503 AN: 17976

American (AMR) AF: 0.385 AC: 15656 AN: 40650

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2090 AN: 20496

East Asian (EAS) AF: 0.289 AC: 10350 AN: 35874

South Asian (SAS) AF: 0.249 AC: 16814 AN: 67468

European-Finnish (FIN) AF: 0.164 AC: 8413 AN: 51268

Middle Eastern (MID) AF: 0.127 AC: 534 AN: 4206

European-Non Finnish (NFE) AF: 0.132 AC: 53379 AN: 402962

Other (OTH) AF: 0.143 AC: 4885 AN: 34238

GnomAD4 genome AF: 0.130 AC: 19719 AN: 151466 Hom.: 1820 Cov.: 32 AF XY: 0.138 AC XY: 10186 AN XY: 73962

African (AFR) AF: 0.0285 AC: 1178 AN: 41310

American (AMR) AF: 0.288 AC: 4381 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0955 AC: 331 AN: 3466

East Asian (EAS) AF: 0.277 AC: 1421 AN: 5134

South Asian (SAS) AF: 0.261 AC: 1248 AN: 4782

European-Finnish (FIN) AF: 0.173 AC: 1796 AN: 10406

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.132 AC: 8975 AN: 67834

Other (OTH) AF: 0.147 AC: 309 AN: 2104

Alfa AF: 0.0579 Hom.: 72

Bravo AF: 0.134

Asia WGS AF: 0.238 AC: 824 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.94
DANN	Benign	0.50
PhyloP100		-0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV51850451;