chr12-100510669-AT-A

Variant names:

• chr12-100510669-AT-A
• rs79532857
• NM_001206979.2:c.80-108delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001206979.2(NR1H4):​c.80-108delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 912,988 control chromosomes in the GnomAD database, including 1,884 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (331 hom., cov: 31)
  • Exomes 𝑓: 0.020 (1553 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.362
• 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 -10 ACMG points.

• BP6: Variant 12-100510669-AT-A is Benign according to our data. Variant chr12-100510669-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1260312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

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.80-108delT		intron	N/A	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.110-108delT		intron	N/A	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.110-108delT		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.80-108delT		intron	N/A	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.110-108delT		intron	N/A	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.110-108delT		intron	N/A	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5117 AN: 148788 Hom.: 328 Cov.: 31

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0681

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00183

Gnomad OTH AF: 0.0350

GnomAD4 exome AF: 0.0201 AC: 15354 AN: 764118 Hom.: 1553 AF XY: 0.0192 AC XY: 7679 AN XY: 400082

African (AFR) AF: 0.0512 AC: 984 AN: 19232

American (AMR) AF: 0.0956 AC: 3256 AN: 34072

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 35 AN: 20410

East Asian (EAS) AF: 0.247 AC: 7798 AN: 31518

South Asian (SAS) AF: 0.0149 AC: 991 AN: 66352

European-Finnish (FIN) AF: 0.0160 AC: 718 AN: 44808

Middle Eastern (MID) AF: 0.00567 AC: 20 AN: 3526

European-Non Finnish (NFE) AF: 0.00108 AC: 551 AN: 508036

Other (OTH) AF: 0.0277 AC: 1001 AN: 36164

GnomAD4 genome AF: 0.0344 AC: 5118 AN: 148870 Hom.: 331 Cov.: 31 AF XY: 0.0377 AC XY: 2734 AN XY: 72612

African (AFR) AF: 0.0567 AC: 2289 AN: 40350

American (AMR) AF: 0.0681 AC: 1007 AN: 14792

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3452

East Asian (EAS) AF: 0.279 AC: 1383 AN: 4960

South Asian (SAS) AF: 0.0220 AC: 105 AN: 4768

European-Finnish (FIN) AF: 0.0138 AC: 133 AN: 9656

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00183 AC: 124 AN: 67648

Other (OTH) AF: 0.0342 AC: 70 AN: 2046

Alfa AF: 0.00247 Hom.: 1

Asia WGS AF: 0.144 AC: 501 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=97/3	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: rs79532857; hg19: chr12-100904447;