rs199611189

Positions:

• chrX-153954546-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.3853G>A​(p.Val1285Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,209,873 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 7 hem., cov: 25)
  • Exomes 𝑓: 0.00011 (0 hom. 37 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.829

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HCFC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.038769215).
• BP6: Variant X-153954546-C-T is Benign according to our data. Variant chrX-153954546-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 532002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.3853G>A	p.Val1285Met	missense_variant	17/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.3853G>A	p.Val1285Met	missense_variant	17/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.3853G>A	p.Val1285Met	missense_variant	17/26	5		A2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 112049 Hom.: 0 Cov.: 25 AF XY: 0.000204 AC XY: 7 AN XY: 34271

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

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: 0.0000189

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000283 AC: 51 AN: 180499 Hom.: 0 AF XY: 0.000224 AC XY: 15 AN XY: 66959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00102

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: 0.000249

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.000111 AC: 122 AN: 1097824 Hom.: 0 Cov.: 34 AF XY: 0.000102 AC XY: 37 AN XY: 363326

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000994

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: 0.0000915

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000125 AC: 14 AN: 112049 Hom.: 0 Cov.: 25 AF XY: 0.000204 AC XY: 7 AN XY: 34271

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.0000409 Hom.: 1

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000151 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.00

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.038
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.10	B;.
Vest4		0.13
MVP		0.18
MPC		0.55
ClinPred		0.035	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.081
gMVP		0.42

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: rs199611189; hg19: chrX-153219997; COSMIC: COSV60072688; COSMIC: COSV60072688;