rs781783048

Positions:

• chrX-153954246-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_005334.3(HCFC1):​c.4153A>G​(p.Arg1385Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,092,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000012 (0 hom. 5 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.677

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 -6 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=0.073542565).
• BP6: Variant X-153954246-T-C is Benign according to our data. Variant chrX-153954246-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582050.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4153A>G	p.Arg1385Gly	missense_variant	17/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4153A>G	p.Arg1385Gly	missense_variant	17/26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.4153A>G	p.Arg1385Gly	missense_variant	17/26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 175884 Hom.: 0 AF XY: 0.0000157 AC XY: 1 AN XY: 63518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1092984 Hom.: 0 Cov.: 34 AF XY: 0.0000139 AC XY: 5 AN XY: 359276

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: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.088	T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.036
Sift	Benign	0.38	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.29		Loss of solvent accessibility (P = 0.002);Loss of solvent accessibility (P = 0.002);
MVP		0.17
MPC		0.70
ClinPred		0.032	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.44

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: rs781783048; hg19: chrX-153219697; COSMIC: COSV60074088; COSMIC: COSV60074088;