rs782484757

chrX-153954709-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005334.3(HCFC1):c.3690G>A(p.Ala1230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 1,192,786 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.000081 (0 hom. 34 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.157

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-153954709-C-T is Benign according to our data. Variant chrX-153954709-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211135.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=-0.157 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.3690G>A	p.Ala1230=	synonymous_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.3690G>A	p.Ala1230=	synonymous_variant	17/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.3690G>A	p.Ala1230=	synonymous_variant	17/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 12 AN: 112894 Hom.: 0 Cov.: 25 AF XY: 0.0000285 AC XY: 1 AN XY: 35048

Gnomad AFR AF: 0.000128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000711 AC: 10 AN: 140674 Hom.: 0 AF XY: 0.0000455 AC XY: 2 AN XY: 43918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000431

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: 0.000121

Gnomad OTH exome AF: 0.000541

GnomAD4 exome AF: 0.0000815 AC: 88 AN: 1079892 Hom.: 0 Cov.: 34 AF XY: 0.0000968 AC XY: 34 AN XY: 351396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000341

Gnomad4 SAS exome AF: 0.0000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000924

Gnomad4 OTH exome AF: 0.000176

GnomAD4 genome AF: 0.000106 AC: 12 AN: 112894 Hom.: 0 Cov.: 25 AF XY: 0.0000285 AC XY: 1 AN XY: 35048

Gnomad4 AFR AF: 0.000128

Gnomad4 AMR AF: 0.000184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 04, 2015

- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.2
Dann	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782484757; hg19: chrX-153220160;