12-100537066-A-G

Variant names:

• chr12-100537066-A-G
• rs78840164
• NM_001206979.2:c.931+19A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001206979.2(NR1H4):​c.931+19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,269,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 0.0000024 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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.931+19A>G		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.961+19A>G		intron	N/A	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.949+19A>G		intron	N/A	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.931+19A>G		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.961+19A>G		intron	N/A	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.949+19A>G		intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 241098 AF XY: 0.00000764

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: 0.00000236 AC: 3 AN: 1269578 Hom.: 0 Cov.: 18 AF XY: 0.00000312 AC XY: 2 AN XY: 641514

African (AFR) AF: 0.00 AC: 0 AN: 29554

American (AMR) AF: 0.00 AC: 0 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24682

East Asian (EAS) AF: 0.00 AC: 0 AN: 38576

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5312

European-Non Finnish (NFE) AF: 0.00000212 AC: 2 AN: 942918

Other (OTH) AF: 0.00 AC: 0 AN: 53914

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.3
DANN	Benign	0.76
PhyloP100		1.1

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: rs78840164; hg19: chr12-100930844;