rs3027888

Positions:

• chrX-153957806-C-T

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.2109G>A​(p.Thr703Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,205,510 control chromosomes in the GnomAD database, including 27 homozygotes. There are 2,678 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 0.0048 (2 hom., 122 hem., cov: 24)
  • Exomes 𝑓: 0.0070 (25 hom. 2556 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.32

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=-0.58).
• BP6: Variant X-153957806-C-T is Benign according to our data. Variant chrX-153957806-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153957806-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.2109G>A	p.Thr703Thr	synonymous_variant	12/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.2109G>A	p.Thr703Thr	synonymous_variant	12/26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.2109G>A	p.Thr703Thr	synonymous_variant	12/26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 543 AN: 112222 Hom.: 3 Cov.: 24 AF XY: 0.00358 AC XY: 123 AN XY: 34384

Gnomad AFR AF: 0.000615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00859

Gnomad FIN AF: 0.000643

Gnomad MID AF: 0.0335

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00729

GnomAD3 exomes AF: 0.00582 AC: 1056 AN: 181479 Hom.: 2 AF XY: 0.00667 AC XY: 449 AN XY: 67363

Gnomad AFR exome AF: 0.000484

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00850

Gnomad FIN exome AF: 0.000943

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00695 AC: 7599 AN: 1093235 Hom.: 25 Cov.: 30 AF XY: 0.00712 AC XY: 2556 AN XY: 358887

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00878

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00746

Gnomad4 OTH exome AF: 0.00629

GnomAD4 genome AF: 0.00480 AC: 539 AN: 112275 Hom.: 2 Cov.: 24 AF XY: 0.00354 AC XY: 122 AN XY: 34447

Gnomad4 AFR AF: 0.000614

Gnomad4 AMR AF: 0.00187

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00824

Gnomad4 FIN AF: 0.000643

Gnomad4 NFE AF: 0.00754

Gnomad4 OTH AF: 0.00719

Alfa AF: 0.00891 Hom.: 78

Bravo AF: 0.00435

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 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. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

HCFC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

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

not provided Benign:1

Likely 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	-0.58
CADD	Benign	0.27
DANN	Benign	0.63
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: rs3027888; hg19: chrX-153223257;