rs61755050

Variant names:

• chr12-100532530-T-C
• rs61755050
• NM_001206979.2:c.518T>C
• NR1H4 p.Met173Thr

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001206979.2(NR1H4):​c.518T>C​(p.Met173Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,614,144 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (22 hom.)
• Consequence: NR1H4 NM_001206979.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 7.66
• Publications: 32 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015372664).
• BP6: Variant 12-100532530-T-C is Benign according to our data. Variant chr12-100532530-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 291196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00364 (555/152330) while in subpopulation NFE AF = 0.00645 (439/68028). AF 95% confidence interval is 0.00595. There are 3 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.518T>C	p.Met173Thr	missense	Exon 5 of 11	NP_001193908.1	Q96RI1-1
	NR1H4	NM_001206993.2		c.548T>C	p.Met183Thr	missense	Exon 3 of 9	NP_001193922.1	Q96RI1-3
	NR1H4	NM_001206992.2		c.548T>C	p.Met183Thr	missense	Exon 3 of 9	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.518T>C	p.Met173Thr	missense	Exon 5 of 11	ENSP00000376712.3	Q96RI1-1
	NR1H4	ENST00000551379.5	TSL:1	c.548T>C	p.Met183Thr	missense	Exon 3 of 9	ENSP00000447149.1	Q96RI1-3
	NR1H4	ENST00000188403.7	TSL:1	c.548T>C	p.Met183Thr	missense	Exon 3 of 9	ENSP00000188403.7	Q96RI1-4

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152212 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00380 AC: 956 AN: 251478 AF XY: 0.00394

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00629

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00535 AC: 7818 AN: 1461814 Hom.: 22 Cov.: 31 AF XY: 0.00528 AC XY: 3843 AN XY: 727218

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00288 AC: 248 AN: 86258

European-Finnish (FIN) AF: 0.00352 AC: 188 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00630 AC: 7010 AN: 1111940

Other (OTH) AF: 0.00434 AC: 262 AN: 60390

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152330 Hom.: 3 Cov.: 33 AF XY: 0.00311 AC XY: 232 AN XY: 74492

African (AFR) AF: 0.00106 AC: 44 AN: 41582

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00645 AC: 439 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00553 Hom.: 12

Bravo AF: 0.00336

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	1	-	NR1H4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.040	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.84
Sift	Benign	0.049	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.64
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61755050;

hg19: chr12-100926308;