Genetic Variant NR1H4:c.1079-285C>G (chr12-100561600-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001206979.2(NR1H4):c.1079-285C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 151,888 control chromosomes in the GnomAD database, including 20,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.51 ( 20922 hom., cov: 32)

Consequence

NR1H4
NM_001206979.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0290

Publications

15 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 (BayesDel_noAF=-0.85).

BP6

Variant 12-100561600-C-G is Benign according to our data. Variant chr12-100561600-C-G is described in ClinVar as Benign. ClinVar VariationId is 1222146.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2 link	c.1079-285C>G		intron_variant	Intron 9 of 10	ENST00000392986.8	NP_001193908.1	Q96RI1-1F1DAL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8 link	c.1079-285C>G		intron_variant	Intron 9 of 10	1	NM_001206979.2	ENSP00000376712.3		Q96RI1-1

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77840

AN:

151768

Hom.:

20905

Cov.:

show subpopulations

Gnomad AFR

AF:

0.410

Gnomad AMI

AF:

0.566

Gnomad AMR

AF:

0.456

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.278

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.501

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.513

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

GnomAD4 genome

AF:

0.513

AC:

77897

AN:

151888

Hom.:

20922

Cov.:

AF XY:

0.504

AC XY:

37392

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.411

AC:

17006

AN:

41412

American (AMR)

AF:

0.455

AC:

6954

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1702

AN:

3470

East Asian (EAS)

AF:

0.278

AC:

1436

AN:

5166

South Asian (SAS)

AF:

0.346

AC:

1665

AN:

4812

European-Finnish (FIN)

AF:

0.501

AC:

5263

AN:

10504

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.620

AC:

42119

AN:

67934

Other (OTH)

AF:

0.513

AC:

1081

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1851

3703

5554

7406

9257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.547

Hom.:

2804

Bravo

AF:

0.507

Asia WGS

AF:

0.293

AC:

1024

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.0

(source)

DANN

Benign

0.32

PhyloP100

-0.029

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over