rs56163822

Variant names:

• chr12-100493323-G-T
• rs56163822
• ENST00000321046.9:n.-1G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000321046.9(NR1H4):​n.-1G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,528,466 control chromosomes in the GnomAD database, including 2,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (160 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1887 hom.)
• Consequence: NR1H4 ENST00000321046.9 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00500
• Publications: 37 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-100493323-G-T is Benign according to our data. Variant chr12-100493323-G-T is described in ClinVar as Benign. ClinVar VariationId is 259641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.-1G>T		5_prime_UTR_variant	Exon 3 of 11	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.-1G>T		5_prime_UTR_variant	Exon 3 of 11	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4694 AN: 152062 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0466 AC: 10444 AN: 224202 AF XY: 0.0499

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0331 AC: 45592 AN: 1376286 Hom.: 1887 Cov.: 23 AF XY: 0.0354 AC XY: 24356 AN XY: 687218

African (AFR) AF: 0.0257 AC: 823 AN: 32038

American (AMR) AF: 0.0367 AC: 1557 AN: 42478

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 1192 AN: 25270

East Asian (EAS) AF: 0.203 AC: 7892 AN: 38918

South Asian (SAS) AF: 0.108 AC: 8878 AN: 82152

European-Finnish (FIN) AF: 0.0217 AC: 1132 AN: 52232

Middle Eastern (MID) AF: 0.0370 AC: 207 AN: 5602

European-Non Finnish (NFE) AF: 0.0211 AC: 21964 AN: 1040360

Other (OTH) AF: 0.0340 AC: 1947 AN: 57236

GnomAD4 genome AF: 0.0308 AC: 4692 AN: 152180 Hom.: 160 Cov.: 32 AF XY: 0.0325 AC XY: 2416 AN XY: 74382

African (AFR) AF: 0.0242 AC: 1004 AN: 41514

American (AMR) AF: 0.0221 AC: 338 AN: 15274

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

East Asian (EAS) AF: 0.146 AC: 755 AN: 5170

South Asian (SAS) AF: 0.116 AC: 560 AN: 4816

European-Finnish (FIN) AF: 0.0222 AC: 235 AN: 10602

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1551 AN: 68012

Other (OTH) AF: 0.0250 AC: 53 AN: 2116

Alfa AF: 0.0297 Hom.: 220

Bravo AF: 0.0304

Asia WGS AF: 0.104 AC: 360 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 04, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		-0.0050
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	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: rs56163822; hg19: chr12-100887101; COSMIC: COSV107351286;