NM_005334.3:c.6074C>G

Variant names:

• chrX-153949381-G-C
• rs1156301874
• NM_005334.3:c.6074C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005334.3(HCFC1):​c.6074C>G​(p.Ser2025Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000903 in 110,795 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• Publications: 0 publications found

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]

HCFC1 Gene-Disease associations (from GenCC):

• methylmalonic acidemia with homocystinuria, type cblX

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1977317).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.6074C>G	p.Ser2025Cys	missense	Exon 26 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.6215C>G	p.Ser2072Cys	missense	Exon 26 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.6209C>G	p.Ser2070Cys	missense	Exon 26 of 26	NP_001397634.1	A6NEM2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.6074C>G	p.Ser2025Cys	missense	Exon 26 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.6215C>G	p.Ser2072Cys	missense	Exon 26 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.6209C>G	p.Ser2070Cys	missense	Exon 26 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110795 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000285

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110795 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32995

African (AFR) AF: 0.00 AC: 0 AN: 30383

American (AMR) AF: 0.00 AC: 0 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2579

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5917

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52810

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.097
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.042	D
Polyphen		0.94	P
Vest4		0.25
MutPred		0.19		Loss of phosphorylation at S2025 (P = 0.0029)
MVP		0.37
MPC		2.2
ClinPred		0.84	D
GERP RS		5.2
Varity_R		0.33
gMVP		0.82
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs1156301874; hg19: chrX-153214832;