NM_005334.3:c.4475C>G

Variant names:

• chrX-153953629-G-C
• rs782407440
• NM_005334.3:c.4475C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005334.3(HCFC1):​c.4475C>G​(p.Pro1492Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000587 in 1,208,909 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 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 0.0000089 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.000064 (0 hom. 21 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36915582).
• BS2: High Hemizygotes in GnomAdExome4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.4475C>G	p.Pro1492Arg	missense_variant	Exon 18 of 26	5		ENSP00000359001.4
HCFC1	ENST00000444191.5	c.197C>G	p.Pro66Arg	missense_variant	Exon 2 of 10	5		ENSP00000399589.1

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112499 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34633

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000391 AC: 7 AN: 178896 Hom.: 0 AF XY: 0.0000302 AC XY: 2 AN XY: 66282

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000638 AC: 70 AN: 1096410 Hom.: 0 Cov.: 31 AF XY: 0.0000579 AC XY: 21 AN XY: 362472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000748

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112499 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34633

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Dec 09, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HCFC1 c.4475C>G (p.Pro1492Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 178896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4475C>G has been reported in the literature in an individual affected with Methylmalonic Acidemia With Homocystinuria (Zhang_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31998365). ClinVar contains an entry for this variant (Variation ID: 373423). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dec 06, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P1492R variant in the HCFC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P1492R variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P1492R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P1492R as a variant of uncertain significance. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Oct 29, 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
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;T
Sift4G	Benign	0.20	T;T
Polyphen		1.0	D;.
Vest4		0.54
MutPred		0.29		Gain of MoRF binding (P = 0.0051);Gain of MoRF binding (P = 0.0051);
MVP		0.57
MPC		1.5
ClinPred		0.66	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.71
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs782407440; hg19: chrX-153219080;