chrX-153954214-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005334.3(HCFC1):c.4185G>A(p.Ala1395Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,205,918 control chromosomes in the GnomAD database, including 27,269 homozygotes. There are 91,326 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 2573 hom., 7135 hem., cov: 24)

Exomes 𝑓: 0.22 ( 24696 hom. 84191 hem. )

Consequence

HCFC1
NM_005334.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.78

Publications

15 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant X-153954214-C-T is Benign according to our data. Variant chrX-153954214-C-T is described in ClinVar as Benign. ClinVar VariationId is 95280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.78 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4185G>A	p.Ala1395Ala	synonymous_variant	Exon 17 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.4185G>A	p.Ala1395Ala	synonymous_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 link	c.4185G>A	p.Ala1395Ala	synonymous_variant	Exon 17 of 26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 link	c.-94G>A		upstream_gene_variant		5		ENSP00000399589.1	H7C1C4

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

23129

AN:

109666

Hom.:

2567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.0666

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.761

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.254

GnomAD2 exomes

AF:

0.328

AC:

58117

AN:

177373

AF XY:

0.325

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.592

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.762

Gnomad FIN exome

AF:

0.181

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.220

AC:

241644

AN:

1096205

Hom.:

24696

Cov.:

AF XY:

0.232

AC XY:

84191

AN XY:

362177

show subpopulations

African (AFR)

AF:

0.108

AC:

2836

AN:

26380

American (AMR)

AF:

0.572

AC:

20016

AN:

34976

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

5501

AN:

19346

East Asian (EAS)

AF:

0.748

AC:

22582

AN:

30179

South Asian (SAS)

AF:

0.568

AC:

30734

AN:

54084

European-Finnish (FIN)

AF:

0.176

AC:

7004

AN:

39787

Middle Eastern (MID)

AF:

0.381

AC:

1544

AN:

4048

European-Non Finnish (NFE)

AF:

0.166

AC:

139299

AN:

841382

Other (OTH)

AF:

0.264

AC:

12128

AN:

46023

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6881

13762

20644

27525

34406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5644

11288

16932

22576

28220

<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:

0.211

AC:

23136

AN:

109713

Hom.:

2573

Cov.:

AF XY:

0.221

AC XY:

7135

AN XY:

32267

show subpopulations

African (AFR)

AF:

0.111

AC:

3338

AN:

30099

American (AMR)

AF:

0.424

AC:

4434

AN:

10460

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

666

AN:

2612

East Asian (EAS)

AF:

0.760

AC:

2591

AN:

3409

South Asian (SAS)

AF:

0.590

AC:

1506

AN:

2553

European-Finnish (FIN)

AF:

0.172

AC:

993

AN:

5772

Middle Eastern (MID)

AF:

0.321

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.174

AC:

9097

AN:

52422

Other (OTH)

AF:

0.266

AC:

399

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

563

1126

1689

2252

2815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.203

Hom.:

2672

Bravo

AF:

0.230

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.092

(source)

DANN

Benign

0.45

PhyloP100

-2.8

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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