rs4073054

chr1-161230697-C-Achr1-161230697-C-Gchr1-161230697-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032174.6(TOMM40L):c.*1602C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,420,154 control chromosomes in the GnomAD database, including 307,756 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (36417 hom., cov: 31)
  • Exomes 𝑓: 0.65 (271339 hom.)
• Consequence: TOMM40L NM_032174.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.285

Genes affected

TOMM40L (HGNC:25756): (translocase of outer mitochondrial membrane 40 like) Predicted to enable protein transmembrane transporter activity. Predicted to be involved in protein import into mitochondrial matrix. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

NR1I3 (HGNC:7969): (nuclear receptor subfamily 1 group I member 3) This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. In addition to drug metabolism, the CAR protein is also reported to regulate genes involved in glucose metabolism, lipid metabolism, cell proliferation, and circadian clock regulation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMM40L	NM_032174.6	c.*1602C>A		3_prime_UTR_variant	10/10	ENST00000367988.8
NR1I3	NM_005122.5	c.917+116G>T		intron_variant		ENST00000367983.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMM40L	ENST00000367988.8	c.*1602C>A		3_prime_UTR_variant	10/10	2	NM_032174.6	P1
NR1I3	ENST00000367983.9	c.917+116G>T		intron_variant		1	NM_005122.5	P4

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104291 AN: 151918 Hom.: 36355 Cov.: 31

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.672

GnomAD4 exome AF: 0.650 AC: 824427 AN: 1268118 Hom.: 271339 Cov.: 17 AF XY: 0.651 AC XY: 411892 AN XY: 632880

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.777

Gnomad4 ASJ exome AF: 0.639

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.621

Gnomad4 NFE exome AF: 0.622

Gnomad4 OTH exome AF: 0.673

GnomAD4 genome AF: 0.687 AC: 104410 AN: 152036 Hom.: 36417 Cov.: 31 AF XY: 0.690 AC XY: 51250 AN XY: 74300

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.714

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.752

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.676

Alfa AF: 0.634 Hom.: 41868

Bravo AF: 0.701

Asia WGS AF: 0.831 AC: 2886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.79
Dann	Benign	0.68

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: rs4073054; hg19: chr1-161200487;