12-100505623-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001206979.2(NR1H4):c.80-5155C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 701,566 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.215

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008201271).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00185 (282/152284) while in subpopulation NFE AF= 0.00321 (218/68016). AF 95% confidence interval is 0.00286. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.80-5155C>G		intron_variant		ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.80-5155C>G		intron_variant		1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00145 AC: 185 AN: 127758 Hom.: 0 AF XY: 0.00137 AC XY: 96 AN XY: 69962

Gnomad AFR exome AF: 0.000822

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000403

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00198 AC: 1087 AN: 549282 Hom.: 2 Cov.: 0 AF XY: 0.00178 AC XY: 530 AN XY: 297370

Gnomad4 AFR exome AF: 0.000507

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000399

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74474

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00321

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.00171

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ExAC AF: 0.000887 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	8.2
Dann	Benign	0.23
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.051
MutPred		0.15		Gain of catalytic residue at H40 (P = 0.0158);Gain of catalytic residue at H40 (P = 0.0158);
MVP		0.16
ClinPred		0.0028	T
GERP RS		-1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs572515785; hg19: chr12-100899401;