rs189548179

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005334.3(HCFC1):c.3794C>T(p.Ser1265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,208,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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. S1265S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 45 hem., cov: 25)

Exomes 𝑓: 0.00090 ( 0 hom. 287 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.67

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

methylmalonic acidemia with homocystinuria, type cblX
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, Illumina
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HCFC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054138303).

BP6

Variant X-153954605-G-A is Benign according to our data. Variant chrX-153954605-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.3794C>T	p.Ser1265Leu	missense_variant	Exon 17 of 26	ENST00000310441.12	NP_005325.2	P51610-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12 link	c.3794C>T	p.Ser1265Leu	missense_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7		P51610-1
HCFC1	ENST00000369984.4 link	c.3794C>T	p.Ser1265Leu	missense_variant	Exon 17 of 26	5		ENSP00000359001.4		A6NEM2

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

176

AN:

112645

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00406

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000645

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000659

Gnomad OTH

AF:

0.00196

GnomAD2 exomes

AF:

0.000736

AC:

130

AN:

176610

AF XY:

0.000734

show subpopulations

Gnomad AFR exome

AF:

0.00409

Gnomad AMR exome

AF:

0.000295

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000615

Gnomad OTH exome

AF:

0.000923

GnomAD4 exome

AF:

0.000904

AC:

990

AN:

1095305

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

287

AN XY:

361129

show subpopulations

African (AFR)

AF:

0.00303

AC:

AN:

26362

American (AMR)

AF:

0.000371

AC:

AN:

35079

Ashkenazi Jewish (ASJ)

AF:

0.00224

AC:

AN:

19235

East Asian (EAS)

AF:

0.00

AC:

AN:

30176

South Asian (SAS)

AF:

0.00

AC:

AN:

54000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39803

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.000946

AC:

795

AN:

840557

Other (OTH)

AF:

0.00128

AC:

AN:

45973

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00155

AC:

175

AN:

112696

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

34886

show subpopulations

African (AFR)

AF:

0.00402

AC:

125

AN:

31095

American (AMR)

AF:

0.000645

AC:

AN:

10860

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6287

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000659

AC:

AN:

53077

Other (OTH)

AF:

0.00194

AC:

AN:

1548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00138

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.000695

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 12, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic developmental and epileptic encephalopathy

Benign:1

Jun 21, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 30, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;T

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;.

PhyloP100

1.7

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.079

Sift

Benign

0.14

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0

B;.

Vest4

0.048

MVP

0.14

MPC

0.48

ClinPred

0.0045

GERP RS

4.2

PromoterAI

0.015

Neutral

(source)

Varity_R

0.037

gMVP

0.46

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over