12-100493341-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001206979.2(NR1H4):c.18T>C(p.Asn6=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000193 in 1,572,162 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NR1H4 NM_001206979.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.14

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-100493341-T-C is Benign according to our data. Variant chr12-100493341-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290853.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000597 (91/152328) while in subpopulation AFR AF= 0.00192 (80/41574). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1H4	NM_001206979.2	c.18T>C	p.Asn6=	synonymous_variant	3/11	ENST00000392986.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1H4	ENST00000392986.8	c.18T>C	p.Asn6=	synonymous_variant	3/11	1	NM_001206979.2	A1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000201 AC: 46 AN: 229132 Hom.: 0 AF XY: 0.000195 AC XY: 24 AN XY: 123236

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.0000919

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.000150 AC: 213 AN: 1419834 Hom.: 0 Cov.: 25 AF XY: 0.000143 AC XY: 101 AN XY: 706682

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74482

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000676

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	8.7
Dann	Benign	0.73

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: rs140648896; hg19: chr12-100887119;