rs17030240

Variant names:

• chr12-100503438-C-T
• rs17030240
• ENST00000551379.5:c.51C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-100503438-C-T
• chr12-100503438-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001206993.2(NR1H4):​c.51C>T​(p.His17His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,597,766 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (83 hom.)
• Consequence: NR1H4 NM_001206993.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-100503438-C-T is Benign according to our data. Variant chr12-100503438-C-T is described in ClinVar as Benign. ClinVar VariationId is 1224977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206993.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.80-7340C>T		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.51C>T	p.His17His	synonymous	Exon 1 of 9	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.51C>T	p.His17His	synonymous	Exon 1 of 9	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000551379.5	TSL:1	c.51C>T	p.His17His	synonymous	Exon 1 of 9	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.51C>T	p.His17His	synonymous	Exon 1 of 9	ENSP00000188403.7	Q96RI1-4
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.80-7340C>T		intron	N/A	ENSP00000376712.3	Q96RI1-1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2651 AN: 152172 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00645 AC: 1474 AN: 228658 AF XY: 0.00556

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.00673

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.00315 AC: 4555 AN: 1445476 Hom.: 83 Cov.: 30 AF XY: 0.00302 AC XY: 2171 AN XY: 719410

African (AFR) AF: 0.0603 AC: 2015 AN: 33430

American (AMR) AF: 0.00824 AC: 368 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 572 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86166

European-Finnish (FIN) AF: 0.0000263 AC: 1 AN: 37982

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5760

European-Non Finnish (NFE) AF: 0.000948 AC: 1054 AN: 1111460

Other (OTH) AF: 0.00722 AC: 435 AN: 60246

GnomAD4 genome AF: 0.0174 AC: 2656 AN: 152290 Hom.: 61 Cov.: 32 AF XY: 0.0166 AC XY: 1233 AN XY: 74486

African (AFR) AF: 0.0542 AC: 2250 AN: 41540

American (AMR) AF: 0.0122 AC: 186 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0119 Hom.: 15

Bravo AF: 0.0207

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00262

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.61
DANN	Benign	0.56
PhyloP100		-1.6
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism

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: rs17030240; hg19: chr12-100897216;