dbSNP rs11110395: NR1H4:c.79+1484G>T (chr12-100494886-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001206979.2(NR1H4):c.79+1484G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 152,156 control chromosomes in the GnomAD database, including 97 homozygotes. 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: 𝑓 0.028 ( 97 hom., cov: 32)

Consequence

NR1H4
NM_001206979.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

Publications

3 publications found

Variant links:

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)

NR1H4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0283 (4307/152156) while in subpopulation AMR AF = 0.0423 (646/15282). AF 95% confidence interval is 0.0396. There are 97 homozygotes in GnomAd4. There are 2010 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 97 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NR1H4	NM_001206979.2	MANE Select	c.79+1484G>T	intron	N/A	NP_001193908.1
NR1H4	NM_001206977.2		c.79+1484G>T	intron	N/A	NP_001193906.1
NR1H4	NM_005123.4		c.79+1484G>T	intron	N/A	NP_005114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.79+1484G>T	intron	N/A	ENSP00000376712.3
NR1H4	ENST00000548884.5	TSL:1	c.79+1484G>T	intron	N/A	ENSP00000448506.1
NR1H4	ENST00000549996.5	TSL:1	c.79+1484G>T	intron	N/A	ENSP00000448978.1

Frequencies

GnomAD3 genomes

AF:

0.0283

AC:

4307

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0423

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0405

Gnomad OTH

AF:

0.0330

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0283

AC:

4307

AN:

152156

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

2010

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00725

AC:

301

AN:

41510

American (AMR)

AF:

0.0423

AC:

646

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

195

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0131

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0252

AC:

266

AN:

10566

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0405

AC:

2751

AN:

68000

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0288

Hom.:

Bravo

AF:

0.0281

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.20

(source)

DANN

Benign

0.37

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over