X-153949361-C-T

Position:

• chrX-153949361-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005334.3(HCFC1):​c.6094G>A​(p.Ala2032Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,615 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.12747794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.6094G>A	p.Ala2032Thr	missense_variant	26/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.6094G>A	p.Ala2032Thr	missense_variant	26/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.6229G>A	p.Ala2077Thr	missense_variant	26/26	5		ENSP00000359001	A2
HCFC1	ENST00000444191.5	c.1822G>A	p.Ala608Thr	missense_variant	10/10	5		ENSP00000399589

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094615 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 360369

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). This variant has not been reported in the literature in individuals affected with HCFC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2032 of the HCFC1 protein (p.Ala2032Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.070	T;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.11
Sift	Benign	0.40	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0010	B;.
Vest4		0.14
MutPred		0.22		Gain of phosphorylation at A2032 (P = 0.0026);.;
MVP		0.44
MPC		3.0
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.10
gMVP		0.65

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-153214812;