rs144641429
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_005333.5(HCCS):c.5G>A(p.Gly2Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,202,840 control chromosomes in the GnomAD database, including 4 homozygotes. There are 723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., 30 hem., cov: 24)
Exomes 𝑓: 0.0022 ( 4 hom. 693 hem. )
Consequence
HCCS
NM_005333.5 missense
NM_005333.5 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 4.54
Genes affected
HCCS (HGNC:4837): (holocytochrome c synthase) The protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c. Defects in this gene are a cause of microphthalmia syndromic type 7 (MCOPS7). Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM1
In a lipid_moiety_binding_region N-myristoyl glycine (size 0) in uniprot entity CCHL_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.049010843).
BP6
Variant X-11112065-G-A is Benign according to our data. Variant chrX-11112065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129217.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chrX-11112065-G-A is described in Lovd as [Benign]. Variant chrX-11112065-G-A is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 30 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HCCS | NM_005333.5 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | ENST00000380762.5 | NP_005324.3 | |
HCCS | NM_001122608.3 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | NP_001116080.1 | ||
HCCS | NM_001171991.3 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | NP_001165462.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HCCS | ENST00000380762.5 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | 1 | NM_005333.5 | ENSP00000370139.4 | ||
HCCS | ENST00000380763.7 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | 1 | ENSP00000370140.3 | |||
HCCS | ENST00000321143.8 | c.5G>A | p.Gly2Asp | missense_variant | 2/7 | 2 | ENSP00000326579.4 |
Frequencies
GnomAD3 genomes AF: 0.00114 AC: 128AN: 112558Hom.: 0 Cov.: 24 AF XY: 0.000864 AC XY: 30AN XY: 34706
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00131 AC: 241AN: 183368Hom.: 0 AF XY: 0.00136 AC XY: 92AN XY: 67800
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GnomAD4 exome AF: 0.00217 AC: 2363AN: 1090228Hom.: 4 Cov.: 28 AF XY: 0.00195 AC XY: 693AN XY: 356168
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GnomAD4 genome AF: 0.00115 AC: 129AN: 112612Hom.: 0 Cov.: 24 AF XY: 0.000863 AC XY: 30AN XY: 34770
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 14, 2013 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2023 | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 10, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2019 | This alteration is classified as 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. - |
HCCS-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 10, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Intellectual disability Benign:1
Benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;.;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
B;B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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