rs192386572

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005334.3(HCFC1):c.4725C>T(p.Pro1575Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,207,730 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,477 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., 78 hem., cov: 26)

Exomes 𝑓: 0.0039 ( 7 hom. 1399 hem. )

Consequence

HCFC1
NM_005334.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00200

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 -15 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.039).

BP6

Variant X-153952731-G-A is Benign according to our data. Variant chrX-153952731-G-A is described in ClinVar as Benign. ClinVar VariationId is 385436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.002 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4725C>T	p.Pro1575Pro	synonymous_variant	Exon 19 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.4725C>T	p.Pro1575Pro	synonymous_variant	Exon 19 of 26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 link	c.4857C>T	p.Pro1619Pro	synonymous_variant	Exon 19 of 26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 link	c.447C>T	p.Pro149Pro	synonymous_variant	Exon 3 of 10	5		ENSP00000399589.1	H7C1C4

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

307

AN:

113410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000767

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00129

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00438

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00433

Gnomad OTH

AF:

0.00324

GnomAD2 exomes

AF:

0.00279

AC:

493

AN:

176758

AF XY:

0.00268

show subpopulations

Gnomad AFR exome

AF:

0.000497

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00313

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00345

GnomAD4 exome

AF:

0.00394

AC:

4310

AN:

1094265

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

1399

AN XY:

360513

show subpopulations

African (AFR)

AF:

0.000645

AC:

AN:

26349

American (AMR)

AF:

0.00122

AC:

AN:

35116

Ashkenazi Jewish (ASJ)

AF:

0.00238

AC:

AN:

19309

East Asian (EAS)

AF:

0.00

AC:

AN:

30116

South Asian (SAS)

AF:

0.000686

AC:

AN:

53965

European-Finnish (FIN)

AF:

0.00286

AC:

113

AN:

39540

Middle Eastern (MID)

AF:

0.000971

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00466

AC:

3914

AN:

839827

Other (OTH)

AF:

0.00296

AC:

136

AN:

45922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

183

367

550

734

917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.00271

AC:

307

AN:

113465

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

AN XY:

35603

show subpopulations

African (AFR)

AF:

0.000766

AC:

AN:

31342

American (AMR)

AF:

0.00129

AC:

AN:

10887

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3602

South Asian (SAS)

AF:

0.00

AC:

AN:

2792

European-Finnish (FIN)

AF:

0.00438

AC:

AN:

6399

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00433

AC:

231

AN:

53318

Other (OTH)

AF:

0.00321

AC:

AN:

1560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00349

Hom.:

Bravo

AF:

0.00228

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jun 30, 2016

GeneDx

Significance: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. -

Mar 03, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.9

(source)

DANN

Benign

0.39

PhyloP100

0.0020

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