rs144160012

Positions:

• chrX-153950915-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005334.3(HCFC1):​c.5601C>T​(p.Ala1867=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,209,367 control chromosomes in the GnomAD database, including 14 homozygotes. There are 453 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 51 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (13 hom. 402 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.62

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-153950915-G-A is Benign according to our data. Variant chrX-153950915-G-A is described in ClinVar as [Benign]. Clinvar id is 506490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00115 (130/112622) while in subpopulation EAS AF= 0.0325 (116/3571). AF 95% confidence interval is 0.0277. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.5601C>T	p.Ala1867=	synonymous_variant	23/26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.5601C>T	p.Ala1867=	synonymous_variant	23/26	1	NM_005334.3	ENSP00000309555	P2
HCFC1	ENST00000369984.4	c.5736C>T	p.Ala1912=	synonymous_variant	23/26	5		ENSP00000359001	A2
HCFC1	ENST00000444191.5	c.1329C>T	p.Ala443=	synonymous_variant	7/10	5		ENSP00000399589

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 130 AN: 112570 Hom.: 1 Cov.: 24 AF XY: 0.00147 AC XY: 51 AN XY: 34712

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000939

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00317 AC: 575 AN: 181600 Hom.: 8 AF XY: 0.00309 AC XY: 209 AN XY: 67598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0379

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.00107 AC: 1178 AN: 1096745 Hom.: 13 Cov.: 32 AF XY: 0.00111 AC XY: 402 AN XY: 362597

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000808

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00115 AC: 130 AN: 112622 Hom.: 1 Cov.: 24 AF XY: 0.00147 AC XY: 51 AN XY: 34774

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000933

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0325

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000939

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000207 Hom.: 2

Bravo AF: 0.00197

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2017

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.035
DANN	Benign	0.61

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: rs144160012; hg19: chrX-153216366; COSMIC: COSV60074660;