chr1-151848285-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_182578.4(THEM5):c.472C>T(p.His158Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,754 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
THEM5
NM_182578.4 missense
NM_182578.4 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 4.84
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THEM5 | NM_182578.4 | c.472C>T | p.His158Tyr | missense_variant | 4/6 | ENST00000368817.10 | |
C2CD4D-AS1 | NR_024237.2 | n.1031-1948G>A | intron_variant, non_coding_transcript_variant | ||||
THEM5 | XM_011509421.2 | c.472C>T | p.His158Tyr | missense_variant | 4/5 | ||
C2CD4D-AS1 | NR_152846.1 | n.951-1948G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THEM5 | ENST00000368817.10 | c.472C>T | p.His158Tyr | missense_variant | 4/6 | 1 | NM_182578.4 | P1 | |
C2CD4D-AS1 | ENST00000434182.1 | n.354-1948G>A | intron_variant, non_coding_transcript_variant | 5 | |||||
THEM5 | ENST00000453881.2 | c.121C>T | p.His41Tyr | missense_variant | 2/3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250998Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135760
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461614Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727098
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2021 | The c.472C>T (p.H158Y) alteration is located in exon 4 (coding exon 4) of the THEM5 gene. This alteration results from a C to T substitution at nucleotide position 472, causing the histidine (H) at amino acid position 158 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0384);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at