5-157731604-T-C

Position:

chr5-157731604-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_017872.5(THG1L):c.164T>C(p.Val55Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,600,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

THG1L
NM_017872.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 5.68

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-157731604-T-C is Pathogenic according to our data. Variant chr5-157731604-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 441070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.13870406). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
THG1L	NM_017872.5 linkuse as main transcript	c.164T>C	p.Val55Ala	missense_variant	1/6	ENST00000231198.12	NP_060342.2
THG1L	NM_001317824.2 linkuse as main transcript	c.-138T>C		5_prime_UTR_variant	1/6		NP_001304753.1
THG1L	NM_001317825.2 linkuse as main transcript	c.-208T>C		5_prime_UTR_variant	1/6		NP_001304754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THG1L	ENST00000231198.12 linkuse as main transcript	c.164T>C	p.Val55Ala	missense_variant	1/6	1	NM_017872.5	ENSP00000231198	P1
THG1L	ENST00000521655.1 linkuse as main transcript	c.164T>C	p.Val55Ala	missense_variant, NMD_transcript_variant	1/6	2		ENSP00000428387

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000207

AC:

AN:

241352

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

130632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00448

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.0000987

AC:

143

AN:

1448418

Hom.:

Cov.:

AF XY:

0.0000917

AC XY:

AN XY:

719818

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00414

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.000251

GnomAD4 genome

AF:

0.000112

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 28

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 12, 2020	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2021	DNA sequence analysis of the THG1L gene demonstrated a sequence change, c.164T>C, in exon 1 that results in an amino acid change, p.Val55Ala. This sequence change has been described in the gnomAD database with a frequency of 0.45% in the Ashkenazi Jewish subpopulation (dbSNP rs201920319). This sequence change has been previously described in the homozygous state in two Ashkenazi Jewish individuals and an Ashkenazi Jewish family with THG1L-related disorder (PMIDs: 27307223, 31168944) where the variant segregated with the disease phenotype. The p.Val55Ala change affects a highly conserved amino acid residue located in a domain of the THG1L protein that is known to be functional. The p.Val55Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, CADD). Functional studies show p.Val55Ala disrupts mitochondrial function and causes abnormal mitochondrial fragmentation (PMID: 27307223). Collectively this evidence suggests p.Val55Ala is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.71

MVP

0.72

MPC

0.63

ClinPred

0.63

GERP RS

5.8

Varity_R

0.92

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over