rs56163822

chr12-100493323-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206979.2(NR1H4):c.-1G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,528,466 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (160 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1887 hom.)
• Consequence: NR1H4 NM_001206979.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00500

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-100493323-G-T is Benign according to our data. Variant chr12-100493323-G-T is described in ClinVar as [Benign]. Clinvar id is 259641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.-1G>T		5_prime_UTR_variant	3/11	ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.-1G>T		5_prime_UTR_variant	3/11	1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4694 AN: 152062 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0466 AC: 10444 AN: 224202 Hom.: 454 AF XY: 0.0499 AC XY: 6011 AN XY: 120418

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0331 AC: 45592 AN: 1376286 Hom.: 1887 Cov.: 23 AF XY: 0.0354 AC XY: 24356 AN XY: 687218

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.0367

Gnomad4 ASJ exome AF: 0.0472

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0308 AC: 4692 AN: 152180 Hom.: 160 Cov.: 32 AF XY: 0.0325 AC XY: 2416 AN XY: 74382

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0222

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0275 Hom.: 26

Bravo AF: 0.0304

Asia WGS AF: 0.104 AC: 360 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	11
Dann	Benign	0.76
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

Publications

LitVar

Other links and lift over

dbSNP: rs56163822; hg19: chr12-100887101;