rs200081632

Positions:

• chrX-153957378-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005334.3(HCFC1):​c.2289C>T​(p.Pro763=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,206,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (0 hom. 77 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.91

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-153957378-G-A is Benign according to our data. Variant chrX-153957378-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153957378-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.91 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.2289C>T	p.Pro763=	synonymous_variant	13/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.2289C>T	p.Pro763=	synonymous_variant	13/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.2289C>T	p.Pro763=	synonymous_variant	13/26	5		ENSP00000359001	A2

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111578 Hom.: 0 Cov.: 24 AF XY: 0.000118 AC XY: 4 AN XY: 33782

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000278 AC: 50 AN: 179798 Hom.: 0 AF XY: 0.000243 AC XY: 16 AN XY: 65834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000160

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000679

GnomAD4 exome AF: 0.000210 AC: 230 AN: 1094975 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 77 AN XY: 360727

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.000519

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000479

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111629 Hom.: 0 Cov.: 24 AF XY: 0.000118 AC XY: 4 AN XY: 33843

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.000472

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000329

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 2

Bravo AF: 0.000121

EpiCase AF: 0.000437

EpiControl AF: 0.000238

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	HCFC1: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 17, 2015

- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs200081632; hg19: chrX-153222829; COSMIC: COSV100129107; COSMIC: COSV100129107;