rs200997332

Variant names:

• chrX-153955425-C-T
• rs200997332
• NM_005334.3:c.2974G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.2974G>A​(p.Ala992Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000523 in 1,209,390 control chromosomes in the GnomAD database, including 1 homozygotes. There are 203 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., 25 hem., cov: 25)
  • Exomes 𝑓: 0.00052 (1 hom. 178 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.52

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008109778).
• BP6: Variant X-153955425-C-T is Benign according to our data. Variant chrX-153955425-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.2974G>A	p.Ala992Thr	missense_variant	Exon 17 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.2974G>A	p.Ala992Thr	missense_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.2974G>A	p.Ala992Thr	missense_variant	Exon 17 of 26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 60 AN: 112572 Hom.: 0 Cov.: 25 AF XY: 0.000720 AC XY: 25 AN XY: 34724

Gnomad AFR AF: 0.0000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000932

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000799 AC: 143 AN: 178914 Hom.: 1 AF XY: 0.000783 AC XY: 51 AN XY: 65128

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.000614

Gnomad OTH exome AF: 0.000910

GnomAD4 exome AF: 0.000522 AC: 572 AN: 1096764 Hom.: 1 Cov.: 33 AF XY: 0.000491 AC XY: 178 AN XY: 362332

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00677

Gnomad4 NFE exome AF: 0.000313

Gnomad4 OTH exome AF: 0.000652

GnomAD4 genome AF: 0.000533 AC: 60 AN: 112626 Hom.: 0 Cov.: 25 AF XY: 0.000719 AC XY: 25 AN XY: 34788

Gnomad4 AFR AF: 0.0000645

Gnomad4 AMR AF: 0.0000930

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00595

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000422 Hom.: 19

Bravo AF: 0.000253

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.000150 AC: 1

ExAC AF: 0.000956 AC: 116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Benign:1

Mar 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.41	N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.19
Sift	Benign	0.23	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.66	P;.
Vest4		0.36
MVP		0.46
MPC		1.5
ClinPred		0.025	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.65

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: rs200997332; hg19: chrX-153220876; COSMIC: COSV100128717; COSMIC: COSV100128717;