1-161230697-C-A

Variant names:

• chr1-161230697-C-A
• rs4073054
• NM_032174.6:c.*1602C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 63 publications found

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]

NR1I3 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032174.6. 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
	TOMM40L	NM_032174.6	MANE Select	c.*1602C>A		3_prime_UTR	Exon 10 of 10	NP_115550.2
	NR1I3	NM_005122.5	MANE Select	c.917+116G>T		intron	N/A	NP_005113.1	Q14994-2
	TOMM40L	NM_001286373.2		c.*1602C>A		3_prime_UTR	Exon 9 of 9	NP_001273302.1	Q969M1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40L	ENST00000367988.8	TSL:2 MANE Select	c.*1602C>A		3_prime_UTR	Exon 10 of 10	ENSP00000356967.3	Q969M1-1
	NR1I3	ENST00000367983.9	TSL:1 MANE Select	c.917+116G>T		intron	N/A	ENSP00000356962.5	Q14994-2
	NR1I3	ENST00000367979.6	TSL:1	c.944+116G>T		intron	N/A	ENSP00000356958.2	Q14994-8

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

African (AFR) AF: 0.783 AC: 23565 AN: 30110

American (AMR) AF: 0.777 AC: 30624 AN: 39420

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 14244 AN: 22278

East Asian (EAS) AF: 0.929 AC: 35737 AN: 38450

South Asian (SAS) AF: 0.745 AC: 56556 AN: 75898

European-Finnish (FIN) AF: 0.621 AC: 24350 AN: 39196

Middle Eastern (MID) AF: 0.678 AC: 3254 AN: 4796

European-Non Finnish (NFE) AF: 0.622 AC: 599829 AN: 964102

Other (OTH) AF: 0.673 AC: 36268 AN: 53868

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

African (AFR) AF: 0.775 AC: 32169 AN: 41490

American (AMR) AF: 0.714 AC: 10909 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2205 AN: 3472

East Asian (EAS) AF: 0.909 AC: 4709 AN: 5180

South Asian (SAS) AF: 0.752 AC: 3629 AN: 4824

European-Finnish (FIN) AF: 0.628 AC: 6623 AN: 10540

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 42003 AN: 67944

Other (OTH) AF: 0.676 AC: 1426 AN: 2110

Alfa AF: 0.643 Hom.: 95706

Bravo AF: 0.701

Asia WGS AF: 0.831 AC: 2886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.79
DANN	Benign	0.68
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4073054; hg19: chr1-161200487;