rs199798029

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

Scores

4
12

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.17
Variant links:
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]

Genome browser will be placed here

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
HCFC1NM_005334.3 linkuse as main transcriptc.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
HCFC1ENST00000310441.12 linkuse as main transcriptc.4442C>T p.Thr1481Met missense_variant 18/261 NM_005334.3 ENSP00000309555 P2P51610-1
HCFC1ENST00000369984.4 linkuse as main transcriptc.4442C>T p.Thr1481Met missense_variant 18/265 ENSP00000359001 A2
HCFC1ENST00000444191.5 linkuse as main transcriptc.167C>T p.Thr56Met missense_variant 2/105 ENSP00000399589

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
37
AN:
112430
Hom.:
0
Cov.:
24
AF XY:
0.000434
AC XY:
15
AN XY:
34578
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000928
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00813
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000113
Gnomad OTH
AF:
0.000662
GnomAD3 exomes
AF:
0.00115
AC:
207
AN:
180011
Hom.:
1
AF XY:
0.000973
AC XY:
65
AN XY:
66815
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0149
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000374
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000356
AC:
391
AN:
1096944
Hom.:
1
Cov.:
31
AF XY:
0.000334
AC XY:
121
AN XY:
362740
show subpopulations
Gnomad4 AFR exome
AF:
0.0000758
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0107
Gnomad4 SAS exome
AF:
0.0000554
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000535
Gnomad4 OTH exome
AF:
0.000413
GnomAD4 genome
AF:
0.000329
AC:
37
AN:
112480
Hom.:
0
Cov.:
24
AF XY:
0.000433
AC XY:
15
AN XY:
34638
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000927
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00816
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.000654
Alfa
AF:
0.000935
Hom.:
13
Bravo
AF:
0.000638
ExAC
AF:
0.000891
AC:
108

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 providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 15, 2016This 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 providedclinical testingPreventionGenetics, part of Exact SciencesDec 16, 2019This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not provided Benign:1
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.63
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.86
D;D
MetaRNN
Benign
0.0070
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.6
L;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.5
N;N
REVEL
Benign
0.12
Sift
Uncertain
0.015
D;D
Sift4G
Benign
0.073
T;T
Polyphen
0.92
P;.
Vest4
0.20
MVP
0.45
MPC
0.71
ClinPred
0.050
T
GERP RS
5.9
Varity_R
0.10
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199798029; hg19: chrX-153219113; COSMIC: COSV60069972; API