rs192386572

chrX-153952731-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.4725C>T(p.Pro1575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,207,730 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,477 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., 78 hem., cov: 26)
  • Exomes 𝑓: 0.0039 (7 hom. 1399 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00200

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-153952731-G-A is Benign according to our data. Variant chrX-153952731-G-A is described in ClinVar as [Benign]. Clinvar id is 385436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153952731-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.4725C>T	p.Pro1575=	synonymous_variant	19/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.4725C>T	p.Pro1575=	synonymous_variant	19/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.4857C>T	p.Pro1619=	synonymous_variant	19/26	5		A2
HCFC1	ENST00000444191.5	c.450C>T	p.Pro150=	synonymous_variant	3/10	5

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 307 AN: 113410 Hom.: 3 Cov.: 26 AF XY: 0.00219 AC XY: 78 AN XY: 35538

Gnomad AFR AF: 0.000767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00433

Gnomad OTH AF: 0.00324

GnomAD3 exomes AF: 0.00279 AC: 493 AN: 176758 Hom.: 2 AF XY: 0.00268 AC XY: 174 AN XY: 64814

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000643

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00394 AC: 4310 AN: 1094265 Hom.: 7 Cov.: 32 AF XY: 0.00388 AC XY: 1399 AN XY: 360513

Gnomad4 AFR exome AF: 0.000645

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00238

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000686

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00271 AC: 307 AN: 113465 Hom.: 3 Cov.: 26 AF XY: 0.00219 AC XY: 78 AN XY: 35603

Gnomad4 AFR AF: 0.000766

Gnomad4 AMR AF: 0.00129

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00438

Gnomad4 NFE AF: 0.00433

Gnomad4 OTH AF: 0.00321

Alfa AF: 0.00349 Hom.: 27

Bravo AF: 0.00228

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.9
Dann	Benign	0.39

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: rs192386572; hg19: chrX-153218182;