Genetic Variant NR1H4:p.Thr21Thr (chr12-100503450-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_001206993.2(NR1H4):c.63G>A(p.Thr21Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,597,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

NR1H4
NM_001206993.2 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.289

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-100503450-G-A is Benign according to our data. Variant chr12-100503450-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3036545.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.289 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1H4	NM_001206979.2	MANE Select	c.80-7328G>A		intron	N/A	NP_001193908.1	Q96RI1-1
NR1H4	NM_001206993.2		c.63G>A	p.Thr21Thr	synonymous	Exon 1 of 9	NP_001193922.1	Q96RI1-3
NR1H4	NM_001206992.2		c.63G>A	p.Thr21Thr	synonymous	Exon 1 of 9	NP_001193921.1	Q96RI1-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1H4	ENST00000551379.5	TSL:1	c.63G>A	p.Thr21Thr	synonymous	Exon 1 of 9	ENSP00000447149.1	Q96RI1-3
NR1H4	ENST00000188403.7	TSL:1	c.63G>A	p.Thr21Thr	synonymous	Exon 1 of 9	ENSP00000188403.7	Q96RI1-4
NR1H4	ENST00000392986.8	TSL:1 MANE Select	c.80-7328G>A		intron	N/A	ENSP00000376712.3	Q96RI1-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000131

AC:

AN:

228402

AF XY:

0.0000158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000949

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000830

AC:

AN:

1445284

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111328

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000596

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

NR1H4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.31

(source)

DANN

Benign

0.50

PhyloP100

-0.29

PromoterAI

-0.063

Neutral

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over