chr12-100510780-G-T

Variant names:

• chr12-100510780-G-T
• rs115828166
• NM_001206979.2:c.82G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001206979.2(NR1H4):​c.82G>T​(p.Val28Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1H4 NM_001206979.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3705879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.82G>T	p.Val28Phe	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.82G>T	p.Val28Phe	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;.;T;.
Eigen	Benign	-0.030
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;.;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.90	.;.;.;.;L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N;N;N;.;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;.;D;D
Polyphen		0.28, 0.50	.;.;.;.;B;P
Vest4		0.64
MutPred		0.23		.;.;.;.;Loss of catalytic residue at V38 (P = 0.0849);Loss of catalytic residue at V38 (P = 0.0849);
MVP		0.93
MPC		0.65
ClinPred		0.76	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115828166; hg19: chr12-100904558; COSMIC: COSV99499912; COSMIC: COSV99499912;