dbSNP rs11110413: NR1H4:c.832-16T>A (chr12-100536932-T-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001206979.2(NR1H4):c.832-16T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,415,698 control chromosomes in the GnomAD database, including 4,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2555 hom., cov: 33)

Exomes 𝑓: 0.013 ( 2148 hom. )

Consequence

NR1H4
NM_001206979.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.846

Publications

1 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 12-100536932-T-A is Benign according to our data. Variant chr12-100536932-T-A is described in ClinVar as Benign. ClinVar VariationId is 259643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

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.832-16T>A	intron	N/A	NP_001193908.1	Q96RI1-1
NR1H4	NM_001206993.2		c.862-16T>A	intron	N/A	NP_001193922.1	Q96RI1-3
NR1H4	NM_001206992.2		c.850-16T>A	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.832-16T>A	intron	N/A	ENSP00000376712.3	Q96RI1-1
NR1H4	ENST00000551379.5	TSL:1	c.862-16T>A	intron	N/A	ENSP00000447149.1	Q96RI1-3
NR1H4	ENST00000188403.7	TSL:1	c.850-16T>A	intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15956

AN:

152070

Hom.:

2540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.0156

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00375

Gnomad OTH

AF:

0.0746

GnomAD2 exomes

AF:

0.0325

AC:

7149

AN:

220270

AF XY:

0.0260

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.0343

Gnomad EAS exome

AF:

0.0132

Gnomad FIN exome

AF:

0.00546

Gnomad NFE exome

AF:

0.00337

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0135

AC:

17005

AN:

1263510

Hom.:

2148

Cov.:

AF XY:

0.0123

AC XY:

7814

AN XY:

637226

show subpopulations

African (AFR)

AF:

0.373

AC:

10519

AN:

28184

American (AMR)

AF:

0.0306

AC:

1085

AN:

35402

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

780

AN:

23596

East Asian (EAS)

AF:

0.0107

AC:

414

AN:

38540

South Asian (SAS)

AF:

0.00296

AC:

221

AN:

74780

European-Finnish (FIN)

AF:

0.00578

AC:

302

AN:

52266

Middle Eastern (MID)

AF:

0.0304

AC:

145

AN:

4776

European-Non Finnish (NFE)

AF:

0.00200

AC:

1902

AN:

952794

Other (OTH)

AF:

0.0308

AC:

1637

AN:

53172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

617

1233

1850

2466

3083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.105

AC:

16007

AN:

152188

Hom.:

2555

Cov.:

AF XY:

0.101

AC XY:

7532

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.350

AC:

14537

AN:

41488

American (AMR)

AF:

0.0499

AC:

763

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3470

East Asian (EAS)

AF:

0.0156

AC:

AN:

5188

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00651

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00375

AC:

255

AN:

67998

Other (OTH)

AF:

0.0743

AC:

157

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

548

1095

1643

2190

2738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0546

Hom.:

201

Bravo

AF:

0.121

Asia WGS

AF:

0.0520

AC:

178

AN:

3464

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.85

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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