rs782652831

Positions:

• chrX-153952880-C-T

Variant summary

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

The NM_005334.3(HCFC1):​c.4576G>A​(p.Ala1526Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,068,384 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000056 (0 hom. 1 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.313

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 -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HCFC1. . Gene score misZ 5.6341 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability, non-syndromic X-linked intellectual disability, methylmalonic acidemia with homocystinuria, type cblX.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04735458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4576G>A	p.Ala1526Thr	missense_variant	19/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4576G>A	p.Ala1526Thr	missense_variant	19/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.4708G>A	p.Ala1570Thr	missense_variant	19/26	5		ENSP00000359001	A2
HCFC1	ENST00000444191.5	c.301G>A	p.Ala101Thr	missense_variant	3/10	5		ENSP00000399589

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000562 AC: 6 AN: 1068384 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 1 AN XY: 346840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000194

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

Bravo AF: 0.00000756

ExAC AF: 0.0000260 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 23, 2016

- -

Methylmalonic acidemia with homocystinuria, type cblX Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T;T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.058
Sift	Benign	0.080	T;D
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;.
Vest4		0.099
MutPred		0.11		Gain of glycosylation at A1526 (P = 0.0325);.;
MVP		0.21
MPC		0.53
ClinPred		0.031	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.39

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: rs782652831; hg19: chrX-153218331;