dbSNP rs879255644: NR1H4:p.Tyr139_Asn140insLys (chr12-100511115-T-TAAA) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM4_SupportingPP3PP5_Moderate

The NM_001206979.2(NR1H4):c.419_420insAAA(p.Tyr139_Asn140insLys) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NR1H4
NM_001206979.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 8.88

Publications

0 publications found

Variant links:

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)

NR1H4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001206979.2. Strenght limited to Supporting due to length of the change: 1aa.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 12-100511115-T-TAAA is Pathogenic according to our data. Variant chr12-100511115-T-TAAA is described in ClinVar as Pathogenic. ClinVar VariationId is 219162.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1H4	NM_001206979.2	MANE Select	c.419_420insAAA	p.Tyr139_Asn140insLys	disruptive_inframe_insertion	Exon 4 of 11	NP_001193908.1	Q96RI1-1
NR1H4	NM_001206993.2		c.449_450insAAA	p.Tyr149_Asn150insLys	disruptive_inframe_insertion	Exon 2 of 9	NP_001193922.1	Q96RI1-3
NR1H4	NM_001206992.2		c.449_450insAAA	p.Tyr149_Asn150insLys	disruptive_inframe_insertion	Exon 2 of 9	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.419_420insAAA	p.Tyr139_Asn140insLys	disruptive_inframe_insertion	Exon 4 of 11	ENSP00000376712.3	Q96RI1-1
NR1H4	ENST00000551379.5	TSL:1	c.449_450insAAA	p.Tyr149_Asn150insLys	disruptive_inframe_insertion	Exon 2 of 9	ENSP00000447149.1	Q96RI1-3
NR1H4	ENST00000188403.7	TSL:1	c.449_450insAAA	p.Tyr149_Asn150insLys	disruptive_inframe_insertion	Exon 2 of 9	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251464

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cholestasis, progressive familial intrahepatic, 5 (1)

NR1H4-related disorder (1)

Progressive familial intrahepatic cholestasis type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.9

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over