chr11-47259902-G-T

Position:

• chr11-47259902-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005693.4(NR1H3):​c.155G>T​(p.Gly52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,611,938 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0065 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (8 hom.)
• Consequence: NR1H3 NM_005693.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.610

Genes affected

NR1H3 (HGNC:7966): (nuclear receptor subfamily 1 group H member 3) The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032809675).
• BP6: Variant 11-47259902-G-T is Benign according to our data. Variant chr11-47259902-G-T is described in ClinVar as [Benign]. Clinvar id is 779196.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 = 0.00652 (993/152278) while in subpopulation AFR AF= 0.0228 (948/41558). AF 95% confidence interval is 0.0216. There are 14 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 993 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1H3	NM_005693.4	c.155G>T	p.Gly52Val	missense_variant	3/10	ENST00000441012.7	NP_005684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1H3	ENST00000441012.7	c.155G>T	p.Gly52Val	missense_variant	3/10	1	NM_005693.4	ENSP00000387946	P1

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152160 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00174 AC: 424 AN: 244366 Hom.: 5 AF XY: 0.00107 AC XY: 142 AN XY: 133062

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.000995

Gnomad ASJ exome AF: 0.000818

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000365

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000776 AC: 1133 AN: 1459660 Hom.: 8 Cov.: 32 AF XY: 0.000629 AC XY: 457 AN XY: 726072

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.000885

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152278 Hom.: 14 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74452

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000896 Hom.: 2

Bravo AF: 0.00755

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	1.2
DANN	Benign	0.66
DEOGEN2	Benign	0.097	T;.;.;T;T;.;.;.;.;.;T;T;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;.;T;T;T;T;.;T;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.0	.;.;.;.;.;.;L;.;.;.;.;L;.;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	.;N;N;N;N;N;N;N;D;N;N;N;D;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.079	.;T;T;D;T;D;T;T;T;D;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.;B;.;.;.;.;B;.;.;B;B
Vest4		0.15
MVP		0.64
MPC		0.56
ClinPred		0.0028	T
GERP RS		-0.83
Varity_R		0.041
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs41481445; hg19: chr11-47281453;