rs2071133

Positions:

• chrX-153954214-C-T

Variant summary

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

The NM_005334.3(HCFC1):​c.4185G>A​(p.Ala1395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,205,918 control chromosomes in the GnomAD database, including 27,269 homozygotes. There are 91,326 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (2573 hom., 7135 hem., cov: 24)
  • Exomes 𝑓: 0.22 (24696 hom. 84191 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.78

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=-0.88).
• BP6: Variant X-153954214-C-T is Benign according to our data. Variant chrX-153954214-C-T is described in ClinVar as [Benign]. Clinvar id is 95280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153954214-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4185G>A	p.Ala1395=	synonymous_variant	17/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4185G>A	p.Ala1395=	synonymous_variant	17/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.4185G>A	p.Ala1395=	synonymous_variant	17/26	5		ENSP00000359001	A2

Frequencies

GnomAD3 genomes AF: 0.211 AC: 23129 AN: 109666 Hom.: 2567 Cov.: 24 AF XY: 0.221 AC XY: 7130 AN XY: 32210

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0666

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.328 AC: 58117 AN: 177373 Hom.: 9057 AF XY: 0.325 AC XY: 21135 AN XY: 64953

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.762

Gnomad SAS exome AF: 0.573

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.220 AC: 241644 AN: 1096205 Hom.: 24696 Cov.: 34 AF XY: 0.232 AC XY: 84191 AN XY: 362177

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.748

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.211 AC: 23136 AN: 109713 Hom.: 2573 Cov.: 24 AF XY: 0.221 AC XY: 7135 AN XY: 32267

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.760

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.266

Alfa AF: 0.199 Hom.: 2393

Bravo AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
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. -
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. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

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

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	-0.88
CADD	Benign	0.092
DANN	Benign	0.45
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: rs2071133; hg19: chrX-153219665; COSMIC: COSV60069027; COSMIC: COSV60069027;