rs372301724

Variant names:

• chrX-153954553-C-T
• rs372301724
• NM_005334.3:c.3846G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005334.3(HCFC1):​c.3846G>A​(p.Ser1282Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,209,530 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.000042 (0 hom. 20 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.93

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-153954553-C-T is Benign according to our data. Variant chrX-153954553-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435397.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 XLR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.3846G>A	p.Ser1282Ser	synonymous_variant	Exon 17 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.3846G>A	p.Ser1282Ser	synonymous_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.3846G>A	p.Ser1282Ser	synonymous_variant	Exon 17 of 26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.0000537 AC: 6 AN: 111709 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000888 AC: 16 AN: 180264 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000732

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000960

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000419 AC: 46 AN: 1097770 Hom.: 0 Cov.: 34 AF XY: 0.0000551 AC XY: 20 AN XY: 363276

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.0000568 AC: 2 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30186

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54136

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 841983

Other (OTH) AF: 0.000130 AC: 6 AN: 46071

GnomAD4 genome AF: 0.0000537 AC: 6 AN: 111760 Hom.: 0 Cov.: 24 AF XY: 0.000117 AC XY: 4 AN XY: 34084

African (AFR) AF: 0.00 AC: 0 AN: 30788

American (AMR) AF: 0.00 AC: 0 AN: 10769

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00115 AC: 4 AN: 3471

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2662

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52796

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.082
DANN	Benign	0.43
PhyloP100		-3.9
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs372301724; hg19: chrX-153220004; COSMIC: COSV60069735; COSMIC: COSV60069735;