rs199511876

Positions:

chrX-153951449-C-T

Variant summary

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

The ENST00000310441.12(HCFC1):c.5418G>A(p.Met1806Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,209,757 control chromosomes in the GnomAD database, including 2 homozygotes. There are 402 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 (★★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., 23 hem., cov: 24)

Exomes 𝑓: 0.0011 ( 2 hom. 379 hem. )

Consequence

HCFC1
ENST00000310441.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0470

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=0.009080857).

BP6

Variant X-153951449-C-T is Benign according to our data. Variant chrX-153951449-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153951449-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.5418G>A	p.Met1806Ile	missense_variant	22/26	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.5418G>A	p.Met1806Ile	missense_variant	22/26	1	NM_005334.3	ENSP00000309555	P2	P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.5553G>A	p.Met1851Ile	missense_variant	22/26	5		ENSP00000359001	A2
HCFC1	ENST00000444191.5 linkuse as main transcript	c.1146G>A	p.Met382Ile	missense_variant	6/10	5		ENSP00000399589

Frequencies

GnomAD3 genomes

AF:

0.000947

AC:

106

AN:

111960

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

34140

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000847

Gnomad ASJ

AF:

0.000756

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.000743

AC:

135

AN:

181717

Hom.:

AF XY:

0.000814

AC XY:

AN XY:

67573

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.000936

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.00105

AC:

1156

AN:

1097743

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

379

AN XY:

363191

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000511

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.000347

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.000955

GnomAD4 genome

AF:

0.000946

AC:

106

AN:

112014

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

34204

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.000846

Gnomad4 ASJ

AF:

0.000756

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000372

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.000653

Alfa

AF:

0.000795

Hom.:

Bravo

AF:

0.000922

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.000287

AC:

ESP6500EA

AF:

0.00230

AC:

ExAC

AF:

0.000976

AC:

118

EpiCase

AF:

0.00213

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	GeneDx	Jun 18, 2018	- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 05, 2021	- -

HCFC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2022

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

0.12

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.070

T;T

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.14

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.79

N;N

REVEL

Benign

0.028

Sift

Benign

0.060

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

B;.

Vest4

0.090

MutPred

0.20

Gain of methylation at K1807 (P = 0.0224);.;

MVP

0.24

MPC

0.60

ClinPred

0.0071

GERP RS

-2.5

Varity_R

0.099

gMVP

0.45

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