rs78840164

Variant names:

• chr12-100537066-A-C
• rs78840164
• NM_001206979.2:c.931+19A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-100537066-A-C
• chr12-100537066-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206979.2(NR1H4):​c.931+19A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,421,864 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 0 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=-0.75).
• BP6: Variant 12-100537066-A-C is Benign according to our data. Variant chr12-100537066-A-C is described in ClinVar as Benign. ClinVar VariationId is 259644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00434 (661/152300) while in subpopulation AFR AF = 0.0154 (641/41572). AF 95% confidence interval is 0.0144. There are 6 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	NM_001206979.2	MANE Select	c.931+19A>C		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.961+19A>C		intron	N/A	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.949+19A>C		intron	N/A	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.931+19A>C		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.961+19A>C		intron	N/A	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.949+19A>C		intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152182 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00102 AC: 245 AN: 241098 AF XY: 0.000718

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000392 AC: 498 AN: 1269564 Hom.: 2 Cov.: 18 AF XY: 0.000334 AC XY: 214 AN XY: 641504

African (AFR) AF: 0.0147 AC: 434 AN: 29540

American (AMR) AF: 0.000355 AC: 15 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24682

East Asian (EAS) AF: 0.00 AC: 0 AN: 38576

South Asian (SAS) AF: 0.0000630 AC: 5 AN: 79398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5312

European-Non Finnish (NFE) AF: 0.00000424 AC: 4 AN: 942918

Other (OTH) AF: 0.000723 AC: 39 AN: 53914

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152300 Hom.: 6 Cov.: 33 AF XY: 0.00400 AC XY: 298 AN XY: 74458

African (AFR) AF: 0.0154 AC: 641 AN: 41572

American (AMR) AF: 0.00111 AC: 17 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00479

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.0
DANN	Benign	0.76
PhyloP100		1.1
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: rs78840164; hg19: chr12-100930844;