12-100505649-C-T

Variant names:

• chr12-100505649-C-T
• rs10492317
• NM_001206979.2:c.80-5129C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206979.2(NR1H4):​c.80-5129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 699,896 control chromosomes in the GnomAD database, including 2,427 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.068 (675 hom., cov: 32)
  • Exomes 𝑓: 0.052 (1752 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.80-5129C>T		intron_variant	Intron 3 of 10	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.80-5129C>T		intron_variant	Intron 3 of 10	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10402 AN: 151964 Hom.: 674 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0504

GnomAD2 exomes AF: 0.0623 AC: 7921 AN: 127056 AF XY: 0.0648

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0521 AC: 28528 AN: 547814 Hom.: 1752 Cov.: 0 AF XY: 0.0540 AC XY: 16026 AN XY: 296630

African (AFR) AF: 0.158 AC: 2487 AN: 15736

American (AMR) AF: 0.0429 AC: 1486 AN: 34606

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 959 AN: 19954

East Asian (EAS) AF: 0.217 AC: 6932 AN: 31992

South Asian (SAS) AF: 0.112 AC: 6948 AN: 62276

European-Finnish (FIN) AF: 0.0217 AC: 718 AN: 33106

Middle Eastern (MID) AF: 0.0394 AC: 157 AN: 3984

European-Non Finnish (NFE) AF: 0.0237 AC: 7473 AN: 315708

Other (OTH) AF: 0.0449 AC: 1368 AN: 30452

GnomAD4 genome AF: 0.0685 AC: 10415 AN: 152082 Hom.: 675 Cov.: 32 AF XY: 0.0690 AC XY: 5133 AN XY: 74344

African (AFR) AF: 0.156 AC: 6450 AN: 41458

American (AMR) AF: 0.0350 AC: 535 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.146 AC: 754 AN: 5166

South Asian (SAS) AF: 0.118 AC: 565 AN: 4808

European-Finnish (FIN) AF: 0.0223 AC: 236 AN: 10594

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1573 AN: 67990

Other (OTH) AF: 0.0499 AC: 105 AN: 2106

Alfa AF: 0.0383 Hom.: 937

Bravo AF: 0.0746

Asia WGS AF: 0.113 AC: 391 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.50
PhyloP100		-0.57
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: rs10492317; hg19: chr12-100899427;