chrX-153959819-G-C

Variant names:

• chrX-153959819-G-C
• rs782364666
• NM_005334.3:c.1427C>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.1427C>G​(p.Thr476Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000945 in 1,058,680 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T476I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• 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: G2P, Ambry Genetics, Orphanet, 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=0.12065831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.1427C>G	p.Thr476Ser	missense_variant	Exon 8 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.1427C>G	p.Thr476Ser	missense_variant	Exon 8 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.1427C>G	p.Thr476Ser	missense_variant	Exon 8 of 26	5		ENSP00000359001.4
HCFC1	ENST00000461098.1	n.*190C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.45e-7 AC: 1 AN: 1058680 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 341660

African (AFR) AF: 0.00 AC: 0 AN: 25427

American (AMR) AF: 0.00 AC: 0 AN: 31372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16650

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29822

South Asian (SAS) AF: 0.00 AC: 0 AN: 48653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2885

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 820702

Other (OTH) AF: 0.00 AC: 0 AN: 44297

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.048
Sift	Benign	0.33	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.36
MPC		1.1
ClinPred		0.25	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.22
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782364666; hg19: chrX-153225270;