Genetic Variant THEM5:p.Gly234Asp (chr1-151847414-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182578.4(THEM5):c.701G>A(p.Gly234Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

THEM5
NM_182578.4 missense, splice_region

Scores

Splicing: ADA: 0.2973

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.131

Variant links:

Genes affected

THEM5 (HGNC:26755): (thioesterase superfamily member 5) Enables palmitoyl-CoA hydrolase activity. Involved in long-chain fatty-acyl-CoA metabolic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

THEM5 links:

C2CD4D-AS1 (HGNC:54045): (C2CD4D and THEM5 antisense RNA 1)

C2CD4D-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM5	NM_182578.4 link	c.701G>A	p.Gly234Asp	missense_variant, splice_region_variant	Exon 6 of 6	ENST00000368817.10	NP_872384.2	Q8N1Q8
THEM5	XM_011509421.2 link	c.576G>A	p.Lys192Lys	splice_region_variant, synonymous_variant	Exon 5 of 5		XP_011507723.1
C2CD4D-AS1	NR_024237.2 link	n.1031-2819C>T		intron_variant	Intron 4 of 4
C2CD4D-AS1	NR_152846.1 link	n.951-2819C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THEM5	ENST00000368817.10 link	c.701G>A	p.Gly234Asp	missense_variant, splice_region_variant	Exon 6 of 6	1	NM_182578.4	ENSP00000357807.4	Q8N1Q8
THEM5	ENST00000453881.2 link	c.222G>A	p.Lys74Lys	splice_region_variant, synonymous_variant	Exon 3 of 3	4		ENSP00000406809.2	H0Y6P4
C2CD4D-AS1	ENST00000434182.1 link	n.354-2819C>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.701G>A (p.G234D) alteration is located in exon 6 (coding exon 6) of the THEM5 gene. This alteration results from a G to A substitution at nucleotide position 701, causing the glycine (G) at amino acid position 234 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

0.13

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.62

M_CAP

Benign

0.0079

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.22

Sift

Uncertain

0.016

Sift4G

Uncertain

0.020

Polyphen

0.69

Vest4

0.74

MutPred

0.39

Gain of disorder (P = 0.0414);

MVP

0.39

MPC

0.18

ClinPred

0.89

GERP RS

3.2

Varity_R

0.86

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.30

dbscSNV1_RF

Benign

0.26

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over