rs200164926

Variant names:

• chrX-153954240-C-T
• rs200164926
• NM_005334.3:c.4159G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.4159G>A​(p.Val1387Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,206,899 control chromosomes in the GnomAD database, including 1 homozygotes. There are 97 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1387V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., 30 hem., cov: 24)
  • Exomes 𝑓: 0.00020 (1 hom. 67 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.601
• Publications: 0 publications found

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]

HCFC1 Gene-Disease associations (from GenCC):

• methylmalonic acidemia with homocystinuria, type cblX

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006447464).
• BP6: Variant X-153954240-C-T is Benign according to our data. Variant chrX-153954240-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 30 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005334.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	NP_001397634.1	A6NEM2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4159G>A	p.Val1387Met	missense	Exon 17 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.000891 AC: 100 AN: 112190 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000284 AC: 50 AN: 176270 AF XY: 0.000188

Gnomad AFR exome AF: 0.00312

Gnomad AMR exome AF: 0.000111

Gnomad ASJ exome AF: 0.000563

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.000461

GnomAD4 exome AF: 0.000200 AC: 219 AN: 1094656 Hom.: 1 Cov.: 34 AF XY: 0.000186 AC XY: 67 AN XY: 360674

African (AFR) AF: 0.00486 AC: 128 AN: 26351

American (AMR) AF: 0.000115 AC: 4 AN: 34908

Ashkenazi Jewish (ASJ) AF: 0.000782 AC: 15 AN: 19181

East Asian (EAS) AF: 0.00 AC: 0 AN: 30150

South Asian (SAS) AF: 0.000111 AC: 6 AN: 53852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39915

Middle Eastern (MID) AF: 0.00245 AC: 10 AN: 4079

European-Non Finnish (NFE) AF: 0.0000393 AC: 33 AN: 840261

Other (OTH) AF: 0.000500 AC: 23 AN: 45959

GnomAD4 genome AF: 0.000900 AC: 101 AN: 112243 Hom.: 0 Cov.: 24 AF XY: 0.000871 AC XY: 30 AN XY: 34429

African (AFR) AF: 0.00278 AC: 86 AN: 30925

American (AMR) AF: 0.000373 AC: 4 AN: 10734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53098

Other (OTH) AF: 0.00130 AC: 2 AN: 1535

Alfa AF: 0.000337 Hom.: 13

Bravo AF: 0.00117

ESP6500AA AF: 0.00107 AC: 4

ESP6500EA AF: 0.000302 AC: 2

ExAC AF: 0.000322 AC: 39

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	HCFC1-related disorder (1)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.085	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.60
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.058
Sift	Benign	0.044	D
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.14
MPC		0.55
ClinPred		0.0020	T
GERP RS		2.3
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.046
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs200164926; hg19: chrX-153219691;