rs11110413

chr12-100536932-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001206979.2(NR1H4):c.832-16T>A variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.846

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.832-16T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.832-16T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001206979.2	A1

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

GnomAD3 exomes AF: 0.0325 AC: 7149 AN: 220270 Hom.: 983 AF XY: 0.0260 AC XY: 3131 AN XY: 120438

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 SAS exome AF: 0.00276

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

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.0107

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.00578

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.0308

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

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.0499

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.0156

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00651

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.0743

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	13
Dann	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs11110413; hg19: chr12-100930710;