12-100505649-C-T

Position:

• chr12-100505649-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000392986.8(NR1H4):​c.80-5129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 699,896 control chromosomes in the GnomAD database, including 2,427 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 0.068 (675 hom., cov: 32)
  • Exomes 𝑓: 0.052 (1752 hom.)
• Consequence: NR1H4 ENST00000392986.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.80-5129C>T		intron_variant		ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.80-5129C>T		intron_variant		1	NM_001206979.2	ENSP00000376712	A1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10402 AN: 151964 Hom.: 674 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0504

GnomAD3 exomes AF: 0.0623 AC: 7921 AN: 127056 Hom.: 405 AF XY: 0.0648 AC XY: 4514 AN XY: 69610

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0521 AC: 28528 AN: 547814 Hom.: 1752 Cov.: 0 AF XY: 0.0540 AC XY: 16026 AN XY: 296630

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.0429

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0449

GnomAD4 genome AF: 0.0685 AC: 10415 AN: 152082 Hom.: 675 Cov.: 32 AF XY: 0.0690 AC XY: 5133 AN XY: 74344

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.0519

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0499

Alfa AF: 0.0298 Hom.: 228

Bravo AF: 0.0746

Asia WGS AF: 0.113 AC: 391 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.50

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: rs10492317; hg19: chr12-100899427;