rs189548179

chrX-153954605-G-A

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.3794C>T(p.Ser1265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,208,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1265S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 45 hem., cov: 25)
  • Exomes 𝑓: 0.00090 (0 hom. 287 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.67

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=0.0054138303).
• BP6: Variant X-153954605-G-A is Benign according to our data. Variant chrX-153954605-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 376776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.3794C>T	p.Ser1265Leu	missense_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.3794C>T	p.Ser1265Leu	missense_variant	17/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.3794C>T	p.Ser1265Leu	missense_variant	17/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 176 AN: 112645 Hom.: 0 Cov.: 25 AF XY: 0.00129 AC XY: 45 AN XY: 34825

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000645

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000659

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000736 AC: 130 AN: 176610 Hom.: 0 AF XY: 0.000734 AC XY: 47 AN XY: 64058

Gnomad AFR exome AF: 0.00409

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.000923

GnomAD4 exome AF: 0.000904 AC: 990 AN: 1095305 Hom.: 0 Cov.: 34 AF XY: 0.000795 AC XY: 287 AN XY: 361129

Gnomad4 AFR exome AF: 0.00303

Gnomad4 AMR exome AF: 0.000371

Gnomad4 ASJ exome AF: 0.00224

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000946

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00155 AC: 175 AN: 112696 Hom.: 0 Cov.: 25 AF XY: 0.00129 AC XY: 45 AN XY: 34886

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.000645

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000659

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.00336 Hom.: 13

Bravo AF: 0.00157

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00138 AC: 5

ESP6500EA AF: 0.00122 AC: 8

ExAC AF: 0.000695 AC: 84

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 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. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	7.1
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.079
Sift	Benign	0.14	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0	B;.
Vest4		0.048
MVP		0.14
MPC		0.48
ClinPred		0.0045	T
GERP RS		4.2
Varity_R		0.037
gMVP		0.46

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: rs189548179; hg19: chrX-153220056; COSMIC: COSV99080104; COSMIC: COSV99080104;