rs376049260

chrX-153954907-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005334.3(HCFC1):c.3492C>T(p.Ser1164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,169,225 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 414 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 0.00079 (0 hom., 29 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (0 hom. 385 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0830

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-153954907-G-A is Benign according to our data. Variant chrX-153954907-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211134.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chrX-153954907-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.083 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.3492C>T	p.Ser1164=	synonymous_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.3492C>T	p.Ser1164=	synonymous_variant	17/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.3492C>T	p.Ser1164=	synonymous_variant	17/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.000792 AC: 89 AN: 112331 Hom.: 0 Cov.: 24 AF XY: 0.000840 AC XY: 29 AN XY: 34519

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000644

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000666 AC: 80 AN: 120161 Hom.: 0 AF XY: 0.000710 AC XY: 23 AN XY: 32401

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000736

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.000305

GnomAD4 exome AF: 0.00109 AC: 1152 AN: 1056841 Hom.: 0 Cov.: 34 AF XY: 0.00113 AC XY: 385 AN XY: 340155

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.000837

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.000792 AC: 89 AN: 112384 Hom.: 0 Cov.: 24 AF XY: 0.000839 AC XY: 29 AN XY: 34582

Gnomad4 AFR AF: 0.000258

Gnomad4 AMR AF: 0.000184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000644

Gnomad4 NFE AF: 0.00142

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000651 Hom.: 4

Bravo AF: 0.000722

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2016	- -

HCFC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.3
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs376049260; hg19: chrX-153220358;