12-100493324-A-T

Position:

• chr12-100493324-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001206979.2(NR1H4):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,381,576 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: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.1A>T	p.Met1?	start_lost	3/11	ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.1A>T	p.Met1?	start_lost	3/11	1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1381576 Hom.: 0 Cov.: 23 AF XY: 0.00000290 AC XY: 2 AN XY: 689566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000485

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	12
DANN	Benign	0.73
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.90	D;.;.;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.37	N;.;N;N;.;D
REVEL	Uncertain	0.46
Sift	Benign	0.10	T;.;T;T;.;D
Sift4G	Benign	0.42	T;.;T;T;.;D
Vest4		0.51
MutPred		0.98		Gain of catalytic residue at K4 (P = 0.007);Gain of catalytic residue at K4 (P = 0.007);Gain of catalytic residue at K4 (P = 0.007);Gain of catalytic residue at K4 (P = 0.007);Gain of catalytic residue at K4 (P = 0.007);Gain of catalytic residue at K4 (P = 0.007);
MVP		0.72
ClinPred		0.090	T
GERP RS		-1.3

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: rs138943609; hg19: chr12-100887102;