rs782665288

chrX-153952862-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_005334.3(HCFC1):c.4594G>A(p.Ala1532Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A1532A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.34

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HCFC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.040997088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.4594G>A	p.Ala1532Thr	missense_variant	19/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.4594G>A	p.Ala1532Thr	missense_variant	19/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.4726G>A	p.Ala1576Thr	missense_variant	19/26	5		A2
HCFC1	ENST00000444191.5	c.319G>A	p.Ala107Thr	missense_variant	3/10	5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1069171 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 346331

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ExAC AF: 0.00000859 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.019
Dann	Benign	0.70
DEOGEN2	Benign	0.081	T;T
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.030
Sift	Benign	0.55	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0020	B;.
Vest4		0.016
MutPred		0.16		Gain of phosphorylation at A1532 (P = 0.0623);.;
MVP		0.25
MPC		0.53
ClinPred		0.032	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.042
gMVP		0.43

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: rs782665288; hg19: chrX-153218313;