X-153954909-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005334.3(HCFC1):c.3490T>C(p.Ser1164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,169,617 control chromosomes in the GnomAD database, including 37,426 homozygotes. There are 97,476 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1164T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.38 ( 7971 hom., 12912 hem., cov: 24)

Exomes 𝑓: 0.24 ( 29455 hom. 84564 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.650

Publications

30 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4520427E-6).

BP6

Variant X-153954909-A-G is Benign according to our data. Variant chrX-153954909-A-G is described in ClinVar as Benign. ClinVar VariationId is 95278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.3490T>C	p.Ser1164Pro	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.3490T>C	p.Ser1164Pro	missense_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7		P51610-1
HCFC1	ENST00000369984.4 link	c.3490T>C	p.Ser1164Pro	missense_variant	Exon 17 of 26	5		ENSP00000359001.4		A6NEM2

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

42496

AN:

111025

Hom.:

7962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.686

Gnomad AMI

AF:

0.0682

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.763

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.353

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.407

GnomAD2 exomes

AF:

0.387

AC:

46926

AN:

121239

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.699

Gnomad AMR exome

AF:

0.609

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.760

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

AF:

0.239

AC:

252780

AN:

1058535

Hom.:

29455

Cov.:

AF XY:

0.247

AC XY:

84564

AN XY:

341803

show subpopulations

African (AFR)

AF:

0.694

AC:

17841

AN:

25695

American (AMR)

AF:

0.598

AC:

18126

AN:

30294

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

5320

AN:

18621

East Asian (EAS)

AF:

0.750

AC:

21522

AN:

28704

South Asian (SAS)

AF:

0.572

AC:

29172

AN:

50959

European-Finnish (FIN)

AF:

0.176

AC:

5451

AN:

31026

Middle Eastern (MID)

AF:

0.402

AC:

1341

AN:

3337

European-Non Finnish (NFE)

AF:

0.170

AC:

140243

AN:

825211

Other (OTH)

AF:

0.308

AC:

13764

AN:

44688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

7370

14740

22109

29479

36849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5814

11628

17442

23256

29070

<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:

0.383

AC:

42556

AN:

111082

Hom.:

7971

Cov.:

AF XY:

0.387

AC XY:

12912

AN XY:

33384

show subpopulations

African (AFR)

AF:

0.687

AC:

21007

AN:

30590

American (AMR)

AF:

0.500

AC:

5362

AN:

10732

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

677

AN:

2632

East Asian (EAS)

AF:

0.762

AC:

2593

AN:

3402

South Asian (SAS)

AF:

0.607

AC:

1620

AN:

2670

European-Finnish (FIN)

AF:

0.179

AC:

1077

AN:

6007

Middle Eastern (MID)

AF:

0.359

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.180

AC:

9464

AN:

52637

Other (OTH)

AF:

0.416

AC:

632

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

756

1512

2268

3024

3780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

396

792

1188

1584

1980

<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:

0.253

Hom.:

12897

Bravo

AF:

0.423

TwinsUK

AF:

0.175

AC:

650

ALSPAC

AF:

0.174

AC:

503

ESP6500AA

AF:

0.638

AC:

2283

ESP6500EA

AF:

0.180

AC:

1169

ExAC

AF:

0.332

AC:

37527

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 31, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2015

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. -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

9.5

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.069

T;T

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

N;.

PhyloP100

0.65

PrimateAI

Benign

0.39

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.048

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.049

MPC

0.69

ClinPred

0.00095

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.11

gMVP

0.26

Mutation Taster

=97/3

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