rs190023981

Variant names:

Variant summary

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

The NM_001440843.1(HCFC1):c.2590G>A(p.Ala864Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,210,086 control chromosomes in the GnomAD database, including 3 homozygotes. There are 627 hemizygotes in GnomAD. In-silico tool predicts 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. A864A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 27 hem., cov: 24)

Exomes 𝑓: 0.0017 ( 3 hom. 600 hem. )

Consequence

HCFC1
NM_001440843.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.63

Publications

1 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=0.024316162).

BP6

Variant X-153956670-C-T is Benign according to our data. Variant chrX-153956670-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 27 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440843.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	NM_005334.3	MANE Select	c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	NP_005325.2
HCFC1	NM_001440843.1		c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	NP_001397634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	ENSP00000309555.7
HCFC1	ENST00000925202.1		c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.2590G>A	p.Ala864Thr	missense	Exon 15 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes

AF:

0.000720

AC:

AN:

112425

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

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:

0.00143

Gnomad OTH

AF:

0.000655

GnomAD2 exomes

AF:

0.000722

AC:

131

AN:

181435

AF XY:

0.000651

show subpopulations

Gnomad AFR exome

AF:

0.000242

Gnomad AMR exome

AF:

0.0000731

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.00166

AC:

1819

AN:

1097608

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

600

AN XY:

363206

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

26391

American (AMR)

AF:

0.0000852

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.0000499

AC:

AN:

40109

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00206

AC:

1737

AN:

841979

Other (OTH)

AF:

0.00139

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000720

AC:

AN:

112478

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

34652

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

31014

American (AMR)

AF:

0.00

AC:

AN:

10704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6211

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

53160

Other (OTH)

AF:

0.000647

AC:

AN:

1546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000849

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.00106

AC:

ExAC

AF:

0.000636

AC:

EpiCase

AF:

0.00180

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Methylmalonic acidemia with homocystinuria, type cblX (2)

not provided (2)

HCFC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

PhyloP100

5.6

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Uncertain

0.0010

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.42

MVP

0.62

MPC

2.5

ClinPred

0.10

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.74

Mutation Taster

=87/13

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over