rs3027884

chrX-153955527-T-CchrX-153955527-T-G

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.2872A>G(p.Thr958Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,170,084 control chromosomes in the GnomAD database, including 2 homozygotes. There are 573 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 0.00097 (0 hom., 26 hem., cov: 25)
  • Exomes 𝑓: 0.0014 (2 hom. 547 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.50

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=0.009462446).
• BP6: Variant X-153955527-T-C is Benign according to our data. Variant chrX-153955527-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 211132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153955527-T-C is described in Lovd as [Benign]. Variant chrX-153955527-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.2872A>G	p.Thr958Ala	missense_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.2872A>G	p.Thr958Ala	missense_variant	17/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.2872A>G	p.Thr958Ala	missense_variant	17/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 108 AN: 111715 Hom.: 0 Cov.: 25 AF XY: 0.000765 AC XY: 26 AN XY: 33985

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00449

Gnomad FIN AF: 0.000647

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00112 AC: 162 AN: 144619 Hom.: 0 AF XY: 0.00143 AC XY: 67 AN XY: 46707

Gnomad AFR exome AF: 0.0000842

Gnomad AMR exome AF: 0.0000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.000578

GnomAD4 exome AF: 0.00141 AC: 1488 AN: 1058318 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 547 AN XY: 340676

Gnomad4 AFR exome AF: 0.0000391

Gnomad4 AMR exome AF: 0.0000644

Gnomad4 ASJ exome AF: 0.000122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00397

Gnomad4 FIN exome AF: 0.00147

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.000789

GnomAD4 genome AF: 0.000966 AC: 108 AN: 111766 Hom.: 0 Cov.: 25 AF XY: 0.000764 AC XY: 26 AN XY: 34046

Gnomad4 AFR AF: 0.000228

Gnomad4 AMR AF: 0.0000938

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00450

Gnomad4 FIN AF: 0.000647

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00118 Hom.: 26

Bravo AF: 0.000816

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00225 AC: 15

ExAC AF: 0.00114 AC: 136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

HCFC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.0050	B;.
Vest4		0.49
MVP		0.70
MPC		2.5
ClinPred		0.038	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.84

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: rs3027884; hg19: chrX-153220978;