rs199511876

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005334.3(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
NM_005334.3 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 -16 ACMG points.

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 rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.5418G>A	p.Met1806Ile	missense_variant	Exon 22 of 26	ENST00000310441.12	NP_005325.2	P51610-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCFC1	ENST00000310441.12 link	c.5418G>A	p.Met1806Ile	missense_variant	Exon 22 of 26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 link	c.5553G>A	p.Met1851Ile	missense_variant	Exon 22 of 26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 link	c.1143G>A	p.Met381Ile	missense_variant	Exon 6 of 10	5		ENSP00000399589.1	H7C1C4

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

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:2

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HCFC1-related disorder

Benign:1

Sep 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.

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