Genetic Variant NR1H4:c.80-5155C>G (chr12-100505623-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001206979.2(NR1H4):c.80-5155C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 701,566 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

NR1H4
NM_001206979.2 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.215

Publications

0 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008201271).

BP6

Variant 12-100505623-C-G is Benign according to our data. Variant chr12-100505623-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1298553.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152284) while in subpopulation NFE AF = 0.00321 (218/68016). AF 95% confidence interval is 0.00286. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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	UniProt
NR1H4	NM_001206979.2	MANE Select	c.80-5155C>G	intron	N/A	NP_001193908.1	Q96RI1-1
NR1H4	NM_001206993.2		c.109+2127C>G	intron	N/A	NP_001193922.1	Q96RI1-3
NR1H4	NM_001206992.2		c.109+2127C>G	intron	N/A	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.80-5155C>G	intron	N/A	ENSP00000376712.3	Q96RI1-1
NR1H4	ENST00000551379.5	TSL:1	c.109+2127C>G	intron	N/A	ENSP00000447149.1	Q96RI1-3
NR1H4	ENST00000188403.7	TSL:1	c.109+2127C>G	intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00320

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00145

AC:

185

AN:

127758

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.000822

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00198

AC:

1087

AN:

549282

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

530

AN XY:

297370

show subpopulations

African (AFR)

AF:

0.000507

AC:

AN:

15780

American (AMR)

AF:

0.00133

AC:

AN:

34680

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

20000

East Asian (EAS)

AF:

0.00

AC:

AN:

32064

South Asian (SAS)

AF:

0.000399

AC:

AN:

62584

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

33170

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00278

AC:

880

AN:

316414

Other (OTH)

AF:

0.00157

AC:

AN:

30546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00185

AC:

282

AN:

152284

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41562

American (AMR)

AF:

0.00118

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00321

AC:

218

AN:

68016

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000647

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000887

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.2

(source)

DANN

Benign

0.23

Eigen

Benign

-0.79

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.12

M_CAP

Benign

0.0029

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.97

PhyloP100

-0.21

PROVEAN

Benign

-1.8

REVEL

Benign

0.082

Sift

Uncertain

0.025

Sift4G

Benign

0.15

Vest4

0.051

MutPred

0.15

Gain of catalytic residue at H40 (P = 0.0158)

MVP

0.16

ClinPred

0.0028

GERP RS

-1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over