X-153960183-G-C

Position:

• chrX-153960183-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000310441.12(HCFC1):​c.1085-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,198,814 control chromosomes in the GnomAD database, including 26,825 homozygotes. There are 89,093 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.21 (2561 hom., 7303 hem., cov: 23)
  • Exomes 𝑓: 0.22 (24264 hom. 81790 hem.)
• Consequence: HCFC1 ENST00000310441.12 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.602

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 Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 4 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-153960183-G-C is Benign according to our data. Variant chrX-153960183-G-C is described in ClinVar as [Benign]. Clinvar id is 676217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.1085-22C>G		intron_variant		ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.1085-22C>G		intron_variant		1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.1085-22C>G		intron_variant		5		ENSP00000359001	A2
HCFC1	ENST00000461098.1	n.227-22C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.210 AC: 23304 AN: 111117 Hom.: 2554 Cov.: 23 AF XY: 0.219 AC XY: 7291 AN XY: 33339

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0706

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.329 AC: 53031 AN: 161178 Hom.: 8823 AF XY: 0.328 AC XY: 17020 AN XY: 51850

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.589

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.761

Gnomad SAS exome AF: 0.578

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.218 AC: 236855 AN: 1087643 Hom.: 24264 Cov.: 33 AF XY: 0.231 AC XY: 81790 AN XY: 354713

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.210 AC: 23319 AN: 111171 Hom.: 2561 Cov.: 23 AF XY: 0.219 AC XY: 7303 AN XY: 33403

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.422

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.266

Alfa AF: 0.209 Hom.: 1896

Bravo AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.1
DANN	Benign	0.72
BranchPoint Hunter		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17421; hg19: chrX-153225634;