5-157732973-C-G

Variant names:

• chr5-157732973-C-G
• rs372164394
• NM_017872.5:c.297C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001317825.2(THG1L):​c.-75C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THG1L NM_001317825.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 0 publications found

Genes affected

THG1L (HGNC:26053): (tRNA-histidine guanylyltransferase 1 like) The protein encoded by this gene is a mitochondrial protein that is induced by high levels of glucose and is associated with diabetic nephropathy. The encoded protein appears to increase mitochondrial biogenesis, which could lead to renal fibrosis. Another function of this protein is that of a guanyltransferase, adding GMP to the 5' end of tRNA(His). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

THG1L Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 28

  Inheritance: AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29604644).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317825.2. 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
	THG1L	NM_017872.5	MANE Select	c.297C>G	p.Ile99Met	missense	Exon 2 of 6	NP_060342.2	Q9NWX6
	THG1L	NM_001317825.2		c.-75C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001304754.1	Q9H8R6
	THG1L	NM_001317824.2		c.-5C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001304753.1	B4E366

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THG1L	ENST00000231198.12	TSL:1 MANE Select	c.297C>G	p.Ile99Met	missense	Exon 2 of 6	ENSP00000231198.7	Q9NWX6
	THG1L	ENST00000960053.1		c.213C>G	p.Ile71Met	missense	Exon 2 of 6	ENSP00000630112.1
	THG1L	ENST00000884966.1		c.297C>G	p.Ile99Met	missense	Exon 2 of 5	ENSP00000555025.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.11
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.092
Sift	Benign	0.23	T
Sift4G	Benign	0.24	T
Polyphen		0.45	B
Vest4		0.25
MutPred		0.54		Loss of sheet (P = 0.0817)
MVP		0.58
MPC		0.45
ClinPred		0.63	D
GERP RS		1.7
Varity_R		0.53
gMVP		0.58
Mutation Taster		=65/35	polymorphism

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: rs372164394; hg19: chr5-157159981;