12-100532538-C-G

Variant names:

• chr12-100532538-C-G
• rs113090017
• NM_001206979.2:c.526C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001206979.2(NR1H4):​c.526C>G​(p.Arg176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.526C>G	p.Arg176Gly	missense_variant	Exon 5 of 11	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.526C>G	p.Arg176Gly	missense_variant	Exon 5 of 11	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;.;.;D;.
Eigen	Benign	0.023
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;.;H;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	D;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;D
Polyphen		1.0	.;.;.;D;D
Vest4		0.94
MutPred		0.92		.;.;.;Loss of MoRF binding (P = 0.0102);Loss of MoRF binding (P = 0.0102);
MVP		0.94
MPC		1.4
ClinPred		0.99	D
GERP RS		-0.23
Varity_R		0.88
gMVP		0.94

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: rs113090017; hg19: chr12-100926316;