rs782484757

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_005334.3(HCFC1):c.3690G>A(p.Ala1230Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,192,786 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 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).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 0.000081 ( 0 hom. 34 hem. )

Consequence

HCFC1
NM_005334.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.157

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant X-153954709-C-T is Benign according to our data. Variant chrX-153954709-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211135.

BP7

Synonymous conserved (PhyloP=-0.157 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.3690G>A	p.Ala1230Ala	synonymous_variant	Exon 17 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12 link	c.3690G>A	p.Ala1230Ala	synonymous_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4 link	c.3690G>A	p.Ala1230Ala	synonymous_variant	Exon 17 of 26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

112894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000184

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000711

AC:

AN:

140674

AF XY:

0.0000455

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.000541

GnomAD4 exome

AF:

0.0000815

AC:

AN:

1079892

Hom.:

Cov.:

AF XY:

0.0000968

AC XY:

AN XY:

351396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26017

American (AMR)

AF:

0.0000313

AC:

AN:

31996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19067

East Asian (EAS)

AF:

0.0000341

AC:

AN:

29294

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.0000924

AC:

AN:

833465

Other (OTH)

AF:

0.000176

AC:

AN:

45403

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000106

AC:

AN:

112894

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

35048

show subpopulations

African (AFR)

AF:

0.000128

AC:

AN:

31136

American (AMR)

AF:

0.000184

AC:

AN:

10856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3541

South Asian (SAS)

AF:

0.00

AC:

AN:

2794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53162

Other (OTH)

AF:

0.00

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

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:

0.000214

Hom.:

Bravo

AF:

0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Nov 27, 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

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.2

(source)

DANN

Benign

0.34

PhyloP100

-0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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