chr12-100536932-T-A

Variant names:

• chr12-100536932-T-A
• rs11110413
• NM_001206979.2:c.832-16T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.846
• Publications: 1 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 -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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.832-16T>A		intron	N/A	NP_001193908.1
	NR1H4	NM_001206993.2		c.862-16T>A		intron	N/A	NP_001193922.1
	NR1H4	NM_001206992.2		c.850-16T>A		intron	N/A	NP_001193921.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.832-16T>A		intron	N/A	ENSP00000376712.3
	NR1H4	ENST00000551379.5	TSL:1	c.862-16T>A		intron	N/A	ENSP00000447149.1
	NR1H4	ENST00000188403.7	TSL:1	c.850-16T>A		intron	N/A	ENSP00000188403.7

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15956 AN: 152070 Hom.: 2540 Cov.: 33

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

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.: 18 AF XY: 0.0123 AC XY: 7814 AN XY: 637226

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

GnomAD4 genome AF: 0.105 AC: 16007 AN: 152188 Hom.: 2555 Cov.: 33 AF XY: 0.101 AC XY: 7532 AN XY: 74412

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: 81 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10606

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00375 AC: 255 AN: 67998

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0546 Hom.: 201

Bravo AF: 0.121

Asia WGS AF: 0.0520 AC: 178 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11110413; hg19: chr12-100930710;