12-100503631-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001206979.2(NR1H4):c.80-7147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 848,996 control chromosomes in the GnomAD database, including 10,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (4014 hom., cov: 32)
  • Exomes 𝑓: 0.066 (6188 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0990

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-100503631-A-G is Benign according to our data. Variant chr12-100503631-A-G is described in ClinVar as [Benign]. Clinvar id is 1287710.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.80-7147A>G		intron_variant		ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.80-7147A>G		intron_variant		1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24075 AN: 152010 Hom.: 3996 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.137

GnomAD4 exome AF: 0.0657 AC: 45768 AN: 696868 Hom.: 6188 AF XY: 0.0661 AC XY: 22910 AN XY: 346658

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.0674

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0459

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0905

GnomAD4 genome AF: 0.159 AC: 24126 AN: 152128 Hom.: 4014 Cov.: 32 AF XY: 0.161 AC XY: 11958 AN XY: 74378

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0767

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.0462

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.135

Alfa AF: 0.104 Hom.: 564

Bravo AF: 0.179

Asia WGS AF: 0.304 AC: 1058 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.8
Dann	Benign	0.51

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: rs7973216; hg19: chr12-100897409; COSMIC: COSV51851379;