rs199798029
Positions:
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
The NM_005334.3(HCFC1):c.4442C>T(p.Thr1481Met) variant causes a missense change. The variant allele was found at a frequency of 0.000354 in 1,209,424 control chromosomes in the GnomAD database, including 1 homozygotes. There are 136 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., 15 hem., cov: 24)
Exomes 𝑓: 0.00036 ( 1 hom. 121 hem. )
Consequence
HCFC1
NM_005334.3 missense
NM_005334.3 missense
Scores
4
12
Clinical Significance
Conservation
PhyloP100: 4.17
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 Benign. Variant got -15 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HCFC1. . Gene score misZ 5.6341 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability, non-syndromic X-linked intellectual disability, methylmalonic acidemia with homocystinuria, type cblX.
BP4
Computational evidence support a benign effect (MetaRNN=0.006960392).
BP6
Variant X-153953662-G-A is Benign according to our data. Variant chrX-153953662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 382802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153953662-G-A is described in Lovd as [Benign]. Variant chrX-153953662-G-A is described in Lovd as [Likely_benign].
BS2
High Hemizygotes in GnomAd4 at 15 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HCFC1 | NM_005334.3 | c.4442C>T | p.Thr1481Met | missense_variant | 18/26 | ENST00000310441.12 | NP_005325.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HCFC1 | ENST00000310441.12 | c.4442C>T | p.Thr1481Met | missense_variant | 18/26 | 1 | NM_005334.3 | ENSP00000309555 | P2 | |
HCFC1 | ENST00000369984.4 | c.4442C>T | p.Thr1481Met | missense_variant | 18/26 | 5 | ENSP00000359001 | A2 | ||
HCFC1 | ENST00000444191.5 | c.167C>T | p.Thr56Met | missense_variant | 2/10 | 5 | ENSP00000399589 |
Frequencies
GnomAD3 genomes AF: 0.000329 AC: 37AN: 112430Hom.: 0 Cov.: 24 AF XY: 0.000434 AC XY: 15AN XY: 34578
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GnomAD3 exomes AF: 0.00115 AC: 207AN: 180011Hom.: 1 AF XY: 0.000973 AC XY: 65AN XY: 66815
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GnomAD4 exome AF: 0.000356 AC: 391AN: 1096944Hom.: 1 Cov.: 31 AF XY: 0.000334 AC XY: 121AN XY: 362740
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GnomAD4 genome AF: 0.000329 AC: 37AN: 112480Hom.: 0 Cov.: 24 AF XY: 0.000433 AC XY: 15AN XY: 34638
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
HCFC1-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Methylmalonic acidemia with homocystinuria, type cblX Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
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