Genetic Variant HCFC1:p.Leu1587Val (chrX-153952697-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005334.3(HCFC1):c.4759C>G(p.Leu1587Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1587F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.26

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23304486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4759C>G	p.Leu1587Val	missense_variant	Exon 19 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HCFC1	ENST00000310441.12 link	c.4759C>G	p.Leu1587Val	missense_variant	Exon 19 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4 link	c.4891C>G	p.Leu1631Val	missense_variant	Exon 19 of 26	5		ENSP00000359001.4
HCFC1	ENST00000444191.5 link	c.481C>G	p.Leu161Val	missense_variant	Exon 3 of 10	5		ENSP00000399589.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095599

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361675

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000379

AC:

AN:

26368

American (AMR)

AF:

0.00

AC:

AN:

35106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

30136

South Asian (SAS)

AF:

0.00

AC:

AN:

53920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39617

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841005

Other (OTH)

AF:

0.00

AC:

AN:

45997

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

5.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.096

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.26

T;T

Vest4

0.21

ClinPred

0.96

GERP RS

4.9

Varity_R

0.73

gMVP

0.76

Mutation Taster

=80/20

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

Computational scores

Splicing

Publications

Other links and lift over