5-157731622-A-C

Variant names:

• chr5-157731622-A-C
• rs2113025862
• NM_017872.5:c.182A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017872.5(THG1L):​c.182A>C​(p.Asn61Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THG1L NM_017872.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.69
• 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

ENSG00000309117 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-157731622-A-C is Pathogenic according to our data. Variant chr5-157731622-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1321970.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017872.5. 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.182A>C	p.Asn61Thr	missense	Exon 1 of 6	NP_060342.2	Q9NWX6
	THG1L	NM_001317825.2		c.-190A>C		5_prime_UTR	Exon 1 of 6	NP_001304754.1	Q9H8R6
	THG1L	NM_001317824.2		c.-120A>C		5_prime_UTR	Exon 1 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.182A>C	p.Asn61Thr	missense	Exon 1 of 6	ENSP00000231198.7	Q9NWX6
	THG1L	ENST00000884966.1		c.182A>C	p.Asn61Thr	missense	Exon 1 of 5	ENSP00000555025.1
	THG1L	ENST00000960054.1		c.182A>C	p.Asn61Thr	missense	Exon 1 of 5	ENSP00000630113.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Polyphen		0.30	B
Vest4		0.73
MutPred		0.47		Gain of MoRF binding (P = 0.1349)
MVP		0.55
MPC		0.21
ClinPred		0.98	D
GERP RS		3.4
PromoterAI		-0.093	Neutral
Varity_R		0.73
gMVP		0.47
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2113025862; hg19: chr5-157158630;