1-161230697-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032174.6(TOMM40L):​c.*1602C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,271,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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>G		3_prime_UTR	Exon 10 of 10	NP_115550.2
	NR1I3	NM_005122.5	MANE Select	c.917+116G>C		intron	N/A	NP_005113.1	Q14994-2
	TOMM40L	NM_001286373.2		c.*1602C>G		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>G		3_prime_UTR	Exon 10 of 10	ENSP00000356967.3	Q969M1-1
	NR1I3	ENST00000367983.9	TSL:1 MANE Select	c.917+116G>C		intron	N/A	ENSP00000356962.5	Q14994-2
	NR1I3	ENST00000367979.6	TSL:1	c.944+116G>C		intron	N/A	ENSP00000356958.2	Q14994-8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000157 AC: 2 AN: 1271038 Hom.: 0 Cov.: 17 AF XY: 0.00000158 AC XY: 1 AN XY: 634284

African (AFR) AF: 0.00 AC: 0 AN: 30132

American (AMR) AF: 0.00 AC: 0 AN: 39472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22308

East Asian (EAS) AF: 0.00 AC: 0 AN: 38462

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4814

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 966686

Other (OTH) AF: 0.0000185 AC: 1 AN: 53960

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 95706

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.31
PhyloP100		-0.28

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;