X-153949575-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_005334.3(HCFC1):c.6046C>T(p.Arg2016Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.40

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HCFC1
• PP5: Variant X-153949575-G-A is Pathogenic according to our data. Variant chrX-153949575-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1299214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30411488).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.6046C>T	p.Arg2016Trp	missense_variant	25/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.6046C>T	p.Arg2016Trp	missense_variant	25/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.6181C>T	p.Arg2061Trp	missense_variant	25/26	5		A2
HCFC1	ENST00000444191.5	c.1774C>T	p.Arg592Trp	missense_variant	9/10	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.15		Gain of ubiquitination at K2015 (P = 0.0268);.;
MVP		0.72
MPC		3.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.88
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153215026;