rs190023981

Positions:

• chrX-153956670-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.2590G>A​(p.Ala864Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,210,086 control chromosomes in the GnomAD database, including 3 homozygotes. There are 627 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A864A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 27 hem., cov: 24)
  • Exomes 𝑓: 0.0017 (3 hom. 600 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.63

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCFC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.024316162).
• BP6: Variant X-153956670-C-T is Benign according to our data. Variant chrX-153956670-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153956670-C-T is described in Lovd as [Likely_benign]. Variant chrX-153956670-C-T is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.2590G>A	p.Ala864Thr	missense_variant	15/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.2590G>A	p.Ala864Thr	missense_variant	15/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.2590G>A	p.Ala864Thr	missense_variant	15/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.000720 AC: 81 AN: 112425 Hom.: 0 Cov.: 24 AF XY: 0.000781 AC XY: 27 AN XY: 34589

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000655

GnomAD3 exomes AF: 0.000722 AC: 131 AN: 181435 Hom.: 0 AF XY: 0.000651 AC XY: 44 AN XY: 67541

Gnomad AFR exome AF: 0.000242

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.00166 AC: 1819 AN: 1097608 Hom.: 3 Cov.: 32 AF XY: 0.00165 AC XY: 600 AN XY: 363206

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.0000499

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000720 AC: 81 AN: 112478 Hom.: 0 Cov.: 24 AF XY: 0.000779 AC XY: 27 AN XY: 34652

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000647

Alfa AF: 0.00100 Hom.: 8

Bravo AF: 0.000680

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.00106 AC: 7

ExAC AF: 0.000636 AC: 77

EpiCase AF: 0.00180

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
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	Genetic Services Laboratory, University of Chicago	Jan 20, 2016	- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2019	This variant is associated with the following publications: (PMID: 25595573, 26893841) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

HCFC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.99	D;.
Vest4		0.42
MVP		0.62
MPC		2.5
ClinPred		0.10	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.74

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

Other links and lift over

dbSNP: rs190023981; hg19: chrX-153222121;