12-100493324-A-T

Variant names:

• chr12-100493324-A-T
• rs138943609
• NM_001206979.2:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001206979.2(NR1H4):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450
• Publications: 8 publications found

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]

NR1H4 Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 100493336. Lost 0.009 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206979.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 11	NP_001193908.1
	NR1H4	NM_001206977.2		c.1A>T	p.Met1?	initiator_codon	Exon 4 of 12	NP_001193906.1
	NR1H4	NM_005123.4		c.1A>T	p.Met1?	initiator_codon	Exon 3 of 11	NP_005114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 11	ENSP00000376712.3
	NR1H4	ENST00000548884.5	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 11	ENSP00000448506.1
	NR1H4	ENST00000549996.5	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 10	ENSP00000448978.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 224802 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000290 AC: 4 AN: 1381576 Hom.: 0 Cov.: 23 AF XY: 0.00000290 AC XY: 2 AN XY: 689566

African (AFR) AF: 0.00 AC: 0 AN: 32130

American (AMR) AF: 0.00 AC: 0 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 38968

South Asian (SAS) AF: 0.0000485 AC: 4 AN: 82452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044826

Other (OTH) AF: 0.00 AC: 0 AN: 57384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.55	T
PhyloP100		0.45
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.46
Sift	Benign	0.10	T
Sift4G	Benign	0.42	T
Vest4		0.51
MutPred		0.98		Gain of catalytic residue at K4 (P = 0.007)
MVP		0.72
ClinPred		0.090	T
GERP RS		-1.3
Mutation Taster		=16/184	disease causing

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

Other links and lift over

dbSNP: rs138943609; hg19: chr12-100887102;