rs200081632

Variant names:

• chrX-153957378-G-A
• rs200081632
• NM_005334.3:c.2289C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005334.3(HCFC1):​c.2289C>T​(p.Pro763Pro) 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 1,206,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 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 0.00019 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00021 (0 hom. 77 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.91
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-153957378-G-A is Benign according to our data. Variant chrX-153957378-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 435400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.91 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 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.2289C>T	p.Pro763Pro	synonymous	Exon 13 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.2289C>T	p.Pro763Pro	synonymous	Exon 13 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.2289C>T	p.Pro763Pro	synonymous	Exon 13 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.2289C>T	p.Pro763Pro	synonymous	Exon 13 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.2289C>T	p.Pro763Pro	synonymous	Exon 13 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.2289C>T	p.Pro763Pro	synonymous	Exon 13 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111578 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000329

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 50 AN: 179798 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000679

GnomAD4 exome AF: 0.000210 AC: 230 AN: 1094975 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 77 AN XY: 360727

African (AFR) AF: 0.0000379 AC: 1 AN: 26369

American (AMR) AF: 0.000716 AC: 25 AN: 34898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19309

East Asian (EAS) AF: 0.00 AC: 0 AN: 30076

South Asian (SAS) AF: 0.000130 AC: 7 AN: 53910

European-Finnish (FIN) AF: 0.000519 AC: 21 AN: 40433

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.000183 AC: 154 AN: 839920

Other (OTH) AF: 0.000479 AC: 22 AN: 45935

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111629 Hom.: 0 Cov.: 24 AF XY: 0.000118 AC XY: 4 AN XY: 33843

African (AFR) AF: 0.0000325 AC: 1 AN: 30747

American (AMR) AF: 0.000472 AC: 5 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2634

European-Finnish (FIN) AF: 0.000329 AC: 2 AN: 6087

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 52991

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.000260 Hom.: 2

Bravo AF: 0.000121

EpiCase AF: 0.000437

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.69
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs200081632; hg19: chrX-153222829; COSMIC: COSV100129107; COSMIC: COSV100129107;