rs372516617

Positions:

• chrX-153962302-G-C

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.717C>G​(p.Thr239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,200,762 control chromosomes in the GnomAD database, including 1 homozygotes. There are 293 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 0.00031 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00086 (1 hom. 284 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.55

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=-0.87).
• BP6: Variant X-153962302-G-C is Benign according to our data. Variant chrX-153962302-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 435405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.55 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.717C>G	p.Thr239=	synonymous_variant	5/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.717C>G	p.Thr239=	synonymous_variant	5/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.717C>G	p.Thr239=	synonymous_variant	5/26	5		A2
HCFC1	ENST00000461098.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 35 AN: 112167 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34325

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000564

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000270 AC: 48 AN: 177532 Hom.: 0 AF XY: 0.000250 AC XY: 16 AN XY: 64026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000857 AC: 933 AN: 1088595 Hom.: 1 Cov.: 28 AF XY: 0.000802 AC XY: 284 AN XY: 354257

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000497

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000240

GnomAD4 genome AF: 0.000312 AC: 35 AN: 112167 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34325

Gnomad4 AFR AF: 0.0000973

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000162

Gnomad4 NFE AF: 0.000564

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.000391 Hom.: 4

Bravo AF: 0.000306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2017	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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2016	- -

HCFC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2019

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

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.088
DANN	Benign	0.62
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: rs372516617; hg19: chrX-153227753;