rs199511876

Positions:

• chrX-153951449-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.5418G>A​(p.Met1806Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,209,757 control chromosomes in the GnomAD database, including 2 homozygotes. There are 402 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., 23 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (2 hom. 379 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0470

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCFC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.009080857).
• BP6: Variant X-153951449-C-T is Benign according to our data. Variant chrX-153951449-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153951449-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.5418G>A	p.Met1806Ile	missense_variant	22/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.5418G>A	p.Met1806Ile	missense_variant	22/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.5553G>A	p.Met1851Ile	missense_variant	22/26	5		A2
HCFC1	ENST00000444191.5	c.1146G>A	p.Met382Ile	missense_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 106 AN: 111960 Hom.: 0 Cov.: 24 AF XY: 0.000674 AC XY: 23 AN XY: 34140

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000847

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000743 AC: 135 AN: 181717 Hom.: 1 AF XY: 0.000814 AC XY: 55 AN XY: 67573

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.000936

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00105 AC: 1156 AN: 1097743 Hom.: 2 Cov.: 32 AF XY: 0.00104 AC XY: 379 AN XY: 363191

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000511

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.000347

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.000955

GnomAD4 genome AF: 0.000946 AC: 106 AN: 112014 Hom.: 0 Cov.: 24 AF XY: 0.000672 AC XY: 23 AN XY: 34204

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.000846

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000653

Alfa AF: 0.000795 Hom.: 16

Bravo AF: 0.000922

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.000287 AC: 1

ESP6500EA AF: 0.00230 AC: 15

ExAC AF: 0.000976 AC: 118

EpiCase AF: 0.00213

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

HCFC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.070	T;T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.14	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.79	N;N
REVEL	Benign	0.028
Sift	Benign	0.060	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;.
Vest4		0.090
MutPred		0.20		Gain of methylation at K1807 (P = 0.0224);.;
MVP		0.24
MPC		0.60
ClinPred		0.0071	T
GERP RS		-2.5
Varity_R		0.099
gMVP		0.45

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: rs199511876; hg19: chrX-153216900;