6-55541767-C-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001042406.2(HMGCLL1):āc.259G>Cā(p.Glu87Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,608,728 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 (ā ).
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 32)
Exomes š: 0.0000089 ( 0 hom. )
Consequence
HMGCLL1
NM_001042406.2 missense
NM_001042406.2 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 6.41
Genes affected
HMGCLL1 (HGNC:21359): (3-hydroxy-3-methylglutaryl-CoA lyase like 1) Enables hydroxymethylglutaryl-CoA lyase activity. Involved in ketone body biosynthetic process. Located in several cellular components, including cytosol; endoplasmic reticulum; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity HMGC2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.94
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMGCLL1 | NM_001042406.2 | c.259G>C | p.Glu87Gln | missense_variant | 3/9 | ENST00000274901.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCLL1 | ENST00000274901.9 | c.259G>C | p.Glu87Gln | missense_variant | 3/9 | 1 | NM_001042406.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152088Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247280Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134240
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GnomAD4 exome AF: 0.00000893 AC: 13AN: 1456522Hom.: 0 Cov.: 28 AF XY: 0.00000690 AC XY: 5AN XY: 724690
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74414
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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 | Mar 22, 2023 | The c.349G>C (p.E117Q) alteration is located in exon 4 (coding exon 4) of the HMGCLL1 gene. This alteration results from a G to C substitution at nucleotide position 349, causing the glutamic acid (E) at amino acid position 117 to be replaced by a glutamine (Q). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;.;D
Vest4
MutPred
0.83
.;Loss of sheet (P = 0.0357);.;.;.;.;
MVP
MPC
0.18
ClinPred
D
GERP RS
Varity_R
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