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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
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 VariationId is 373423.

BS2

High Hemizygotes in GnomAdExome4 at 21 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCFC1	NM_005334.3	MANE Select	c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	NP_005325.2	P51610-1
HCFC1	NM_001440843.1		c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	NP_001397634.1	A6NEM2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	ENSP00000309555.7	P51610-1
HCFC1	ENST00000925202.1		c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.4475C>G	p.Pro1492Arg	missense	Exon 18 of 26	ENSP00000359001.4	A6NEM2

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

4.1

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.54

MutPred

0.29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over