rs397515486
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP2PP5
The NM_005334.3(HCFC1):c.218C>T(p.Ala73Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A73T) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
HCFC1
NM_005334.3 missense
NM_005334.3 missense
Scores
4
5
8
Clinical Significance
Conservation
PhyloP100: 9.74
Genes affected
HCFC1 (HGNC:4839): (host cell factor C1) This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]
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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;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-153964703-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66986.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
Missense variant where missense usually causes diseases, HCFC1
PP5
?
Variant X-153964702-G-A is Pathogenic according to our data. Variant chrX-153964702-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66985.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=3}. Variant chrX-153964702-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCFC1 | NM_005334.3 | c.218C>T | p.Ala73Val | missense_variant | 2/26 | ENST00000310441.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCFC1 | ENST00000310441.12 | c.218C>T | p.Ala73Val | missense_variant | 2/26 | 1 | NM_005334.3 | P2 | |
HCFC1 | ENST00000369984.4 | c.218C>T | p.Ala73Val | missense_variant | 2/26 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1073459Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 344387
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
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0
AN:
1073459
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Cov.:
30
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AC XY:
0
AN XY:
344387
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Methylmalonic acidemia with homocystinuria, type cblX Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 25, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HCFC1 protein function. This variant has been observed in individual(s) with cobalamin X deficiency (PMID: 24011988, 25167861). ClinVar contains an entry for this variant (Variation ID: 66985). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 73 of the HCFC1 protein (p.Ala73Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
Cobalamin C disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 12, 2020 | Variant summary: HCFC1 c.218C>T (p.Ala73Val) results in a non-conservative amino acid change located in the the first kelch domain (Yu_2013) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 161726 control chromosomes (gnomAD). c.218C>T has been reported in the literature in individuals affected with Methylmalonic Acidemia With Homocystinuria as well as one individual whose parents were negative for the mutation, suggesting that it arose de novo (Yu_2013, Redin_2014). Functional studies report this variant results in reducing the level of MMACHC expression and in biochemical abnormalities (Yu_2013, Quintana_2014). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 23, 2015 | - - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Jul 25, 2014 | present in the affected brother - |
Disorders of Intracellular Cobalamin Metabolism Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at