rs7138843

Positions:

• chr12-100536917-T-A
• chr12-100536917-T-C

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.832-31T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,248,466 control chromosomes in the GnomAD database, including 14,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4948 hom., cov: 33)
  • Exomes 𝑓: 0.062 (9407 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.106

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=-0.85).
• BP6: Variant 12-100536917-T-A is Benign according to our data. Variant chr12-100536917-T-A is described in ClinVar as [Benign]. Clinvar id is 1246288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.832-31T>A		intron_variant		ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.832-31T>A		intron_variant		1	NM_001206979.2	ENSP00000376712	A1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26043 AN: 151978 Hom.: 4917 Cov.: 33

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0423

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.117 AC: 25714 AN: 219168 Hom.: 3989 AF XY: 0.107 AC XY: 12786 AN XY: 119966

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.440

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0459

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0798

GnomAD4 exome AF: 0.0617 AC: 67609 AN: 1096370 Hom.: 9407 Cov.: 15 AF XY: 0.0621 AC XY: 34851 AN XY: 560980

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.0655

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0894

GnomAD4 genome AF: 0.172 AC: 26110 AN: 152096 Hom.: 4948 Cov.: 33 AF XY: 0.173 AC XY: 12898 AN XY: 74346

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.0423

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.134

Alfa AF: 0.0908 Hom.: 377

Bravo AF: 0.193

Asia WGS AF: 0.318 AC: 1101 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.2
DANN	Benign	0.69

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: rs7138843; hg19: chr12-100930695;