X-153949579-G-A

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.6042C>T(p.Asn2014=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,209,731 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 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 0.00028 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (0 hom. 72 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.65

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=-0.52).
• BP6: Variant X-153949579-G-A is Benign according to our data. Variant chrX-153949579-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167164.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=2.65 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.6042C>T	p.Asn2014=	synonymous_variant	25/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.6042C>T	p.Asn2014=	synonymous_variant	25/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.6177C>T	p.Asn2059=	synonymous_variant	25/26	5		A2
HCFC1	ENST00000444191.5	c.1770C>T	p.Asn590=	synonymous_variant	9/10	5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 31 AN: 112230 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34386

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000508

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000204 AC: 37 AN: 181634 Hom.: 0 AF XY: 0.000148 AC XY: 10 AN XY: 67612

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: 0.000314

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 221 AN: 1097501 Hom.: 0 Cov.: 30 AF XY: 0.000198 AC XY: 72 AN XY: 362875

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: 0.000445

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000276 AC: 31 AN: 112230 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34386

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.0000934

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.000508

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000254 Hom.: 1

Bravo AF: 0.000189

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 21, 2014

- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	8.1
Dann	Benign	0.85

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: rs199953428; hg19: chrX-153215030; COSMIC: COSV60071199; COSMIC: COSV60071199;