X-153953629-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_005334.3(HCFC1):c.4475C>G(p.Pro1492Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000587 in 1,208,909 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1492L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000064 ( 0 hom. 21 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.15

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36915582).

BP6

Variant X-153953629-G-C is Benign according to our data. Variant chrX-153953629-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373423.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High Hemizygotes in GnomAdExome4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 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.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 of 26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 link	c.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 of 26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 link	c.197C>G	p.Pro66Arg	missense_variant	Exon 2 of 10	5		ENSP00000399589.1	H7C1C4

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112499

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000391

AC:

AN:

178896

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000252

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1096410

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

362472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26389

American (AMR)

AF:

0.000142

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39221

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4073

European-Non Finnish (NFE)

AF:

0.0000748

AC:

AN:

841761

Other (OTH)

AF:

0.0000217

AC:

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112499

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34633

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30986

American (AMR)

AF:

0.00

AC:

AN:

10765

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6263

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53169

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Dec 09, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The P1492R variant in the HCFC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P1492R variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1492R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P1492R as a variant of uncertain significance. -

Jun 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HCFC1 c.4475C>G (p.Pro1492Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 178896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4475C>G has been reported in the literature in an individual affected with Methylmalonic Acidemia With Homocystinuria (Zhang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31998365). ClinVar contains an entry for this variant (Variation ID: 373423). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

4.1

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

D;T

Sift4G

Benign

0.20

T;T

Polyphen

1.0

D;.

Vest4

0.54

MutPred

0.29

Gain of MoRF binding (P = 0.0051);Gain of MoRF binding (P = 0.0051);

MVP

0.57

MPC

1.5

ClinPred

0.66

GERP RS

5.9

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.71

gMVP

0.80

Mutation Taster

=61/39

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over