rs190023981

Positions:

chrX-153956670-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

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 (★★).

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.63

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]

HCFC1 links:

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=0.024316162).

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	Protein	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.2590G>A	p.Ala864Thr	missense_variant	15/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12 linkuse as main transcript	c.2590G>A	p.Ala864Thr	missense_variant	15/26	1	NM_005334.3	ENSP00000309555	P2	P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.2590G>A	p.Ala864Thr	missense_variant	15/26	5		ENSP00000359001	A2

Frequencies

GnomAD3 genomes

AF:

0.000720

AC:

AN:

112425

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

34589

show subpopulations

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.:

AF XY:

0.000651

AC XY:

AN XY:

67541

show subpopulations

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.:

Cov.:

AF XY:

0.00165

AC XY:

600

AN XY:

363206

show subpopulations

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:

AN:

112478

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

34652

show subpopulations

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.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.00106

AC:

ExAC

AF:

0.000636

AC:

EpiCase

AF:

0.00180

EpiControl

AF:

0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over