Genetic Variant THEM5:p.Gly159Ser (chr1-151848282-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PP3_ModerateBP6_Moderate

The NM_182578.4(THEM5):c.475G>A(p.Gly159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

THEM5
NM_182578.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.41

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:

Genome browser will be placed here

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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

BP6

Variant 1-151848282-C-T is Benign according to our data. Variant chr1-151848282-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2236922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THEM5	NM_182578.4 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 6	ENST00000368817.10	NP_872384.2	Q8N1Q8
THEM5	XM_011509421.2 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 5		XP_011507723.1
C2CD4D-AS1	NR_024237.2 link	n.1031-1951C>T		intron_variant	Intron 4 of 4
C2CD4D-AS1	NR_152846.1 link	n.951-1951C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THEM5	ENST00000368817.10 link	c.475G>A	p.Gly159Ser	missense_variant	Exon 4 of 6	1	NM_182578.4	ENSP00000357807.4	Q8N1Q8
THEM5	ENST00000453881.2 link	c.121G>A	p.Gly41Ser	missense_variant	Exon 2 of 3	4		ENSP00000406809.2	H0Y6P4
C2CD4D-AS1	ENST00000434182.1 link	n.354-1951C>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250974

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000373

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

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:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000663

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 14, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.4

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.70

Sift

Uncertain

0.021

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.85

MVP

0.75

MPC

0.29

ClinPred

0.95

GERP RS

4.5

Varity_R

0.88

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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