rs200164926

Variant summary

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

The NM_005334.3(HCFC1):c.4159G>A(p.Val1387Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,206,899 control chromosomes in the GnomAD database, including 1 homozygotes. There are 97 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. V1387V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., 30 hem., cov: 24)

Exomes 𝑓: 0.00020 ( 1 hom. 67 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.601

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 where missense usually causes diseases, HCFC1

BP4

Computational evidence support a benign effect (MetaRNN=0.006447464).

BP6

Variant X-153954240-C-T is Benign according to our data. Variant chrX-153954240-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153954240-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.4159G>A	p.Val1387Met	missense_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12 linkuse as main transcript	c.4159G>A	p.Val1387Met	missense_variant	17/26	1	NM_005334.3	P2	P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.4159G>A	p.Val1387Met	missense_variant	17/26	5		A2

Frequencies

GnomAD3 genomes

AF:

0.000891

AC:

100

AN:

112190

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

AN XY:

34366

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000367

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000284

AC:

AN:

176270

Hom.:

AF XY:

0.000188

AC XY:

AN XY:

63882

show subpopulations

Gnomad AFR exome

AF:

0.00312

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.000563

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000539

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000256

Gnomad OTH exome

AF:

0.000461

GnomAD4 exome

AF:

0.000200

AC:

219

AN:

1094656

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

AN XY:

360674

show subpopulations

Gnomad4 AFR exome

AF:

0.00486

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.000782

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000393

Gnomad4 OTH exome

AF:

0.000500

GnomAD4 genome

AF:

0.000900

AC:

101

AN:

112243

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

AN XY:

34429

show subpopulations

Gnomad4 AFR

AF:

0.00278

Gnomad4 AMR

AF:

0.000373

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000368

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.000281

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00107

AC:

ESP6500EA

AF:

0.000302

AC:

ExAC

AF:

0.000322

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely 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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2018	- -

HCFC1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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). -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.91

BayesDel_noAF

Benign

-1.1

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.085

T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.058

Sift

Benign

0.044

D;T

Sift4G

Benign

0.22

T;T

Polyphen

0.0

B;.

Vest4

0.10

MVP

0.14

MPC

0.55

ClinPred

0.0020

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.046

gMVP

0.12

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