rs3027878

Positions:

• chrX-153952914-C-A
• chrX-153952914-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000310441.12(HCFC1):​c.4542G>T​(p.Leu1514=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,178,047 control chromosomes in the GnomAD database, including 21,618 homozygotes. There are 75,804 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1514L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (2174 hom., 6764 hem., cov: 25)
  • Exomes 𝑓: 0.18 (19444 hom. 69040 hem.)
• Consequence: HCFC1 ENST00000310441.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.403

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-153952914-C-A is Benign according to our data. Variant chrX-153952914-C-A is described in ClinVar as [Benign]. Clinvar id is 129222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153952914-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.403 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4542G>T	p.Leu1514=	synonymous_variant	19/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4542G>T	p.Leu1514=	synonymous_variant	19/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.4674G>T	p.Leu1558=	synonymous_variant	19/26	5		ENSP00000359001	A2
HCFC1	ENST00000444191.5	c.267G>T	p.Leu89=	synonymous_variant	3/10	5		ENSP00000399589

Frequencies

GnomAD3 genomes AF: 0.180 AC: 20308 AN: 112628 Hom.: 2176 Cov.: 25 AF XY: 0.194 AC XY: 6762 AN XY: 34812

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.0599

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.321 AC: 40409 AN: 125834 Hom.: 6675 AF XY: 0.335 AC XY: 13487 AN XY: 40268

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.749

Gnomad SAS exome AF: 0.561

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.185 AC: 196960 AN: 1065364 Hom.: 19444 Cov.: 32 AF XY: 0.199 AC XY: 69040 AN XY: 346808

Gnomad4 AFR exome AF: 0.0628

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.180 AC: 20300 AN: 112683 Hom.: 2174 Cov.: 25 AF XY: 0.194 AC XY: 6764 AN XY: 34877

Gnomad4 AFR AF: 0.0701

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.229

Alfa AF: 0.178 Hom.: 2424

Bravo AF: 0.200

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	GeneDx	Dec 02, 2015	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, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.5
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3027878; hg19: chrX-153218365; COSMIC: COSV60075244;