12-100561600-C-G

Variant names:

• chr12-100561600-C-G
• rs35724
• NM_001206979.2:c.1079-285C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0290
• Publications: 15 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: 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	c.1079-285C>G		intron_variant	Intron 9 of 10	ENST00000392986.8	NP_001193908.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77840 AN: 151768 Hom.: 20905 Cov.: 32

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.: 32 AF XY: 0.504 AC XY: 37392 AN XY: 74202

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

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

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
DANN	Benign	0.32
PhyloP100		-0.029
Mutation Taster		=100/0	polymorphism (auto)

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: rs35724; hg19: chr12-100955378;