rs781783048

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005334.3(HCFC1):c.4153A>G(p.Arg1385Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,092,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.000012 ( 0 hom. 5 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.677

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073542565).

BP6

Variant X-153954246-T-C is Benign according to our data. Variant chrX-153954246-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582050.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4153A>G	p.Arg1385Gly	missense_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.4153A>G	p.Arg1385Gly	missense_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 link	c.4153A>G	p.Arg1385Gly	missense_variant	Exon 17 of 26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 link	c.-126A>G		upstream_gene_variant		5		ENSP00000399589.1	H7C1C4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

175884

AF XY:

0.0000157

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1092984

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

359276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26312

American (AMR)

AF:

0.00

AC:

AN:

34854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19132

East Asian (EAS)

AF:

0.00

AC:

AN:

30102

South Asian (SAS)

AF:

0.00

AC:

AN:

53842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

838880

Other (OTH)

AF:

0.00

AC:

AN:

45850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX

Uncertain:1Benign:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.088

T;T

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

N;.

PhyloP100

0.68

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.036

Sift

Benign

0.38

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0

B;.

Vest4

0.10

MutPred

0.29

Loss of solvent accessibility (P = 0.002);Loss of solvent accessibility (P = 0.002);

MVP

0.17

MPC

0.70

ClinPred

0.032

GERP RS

3.6

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.44

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over