rs192386572

Variant names:

• chrX-153952731-G-A
• rs192386572
• NM_005334.3:c.4725C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005334.3(HCFC1):​c.4725C>T​(p.Pro1575Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,207,730 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,477 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., 78 hem., cov: 26)
  • Exomes 𝑓: 0.0039 (7 hom. 1399 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00200
• Publications: 2 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.039).
• BP6: Variant X-153952731-G-A is Benign according to our data. Variant chrX-153952731-G-A is described in ClinVar as Benign. ClinVar VariationId is 385436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 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.4725C>T	p.Pro1575Pro	synonymous	Exon 19 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.4857C>T	p.Pro1619Pro	synonymous	Exon 19 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4857C>T	p.Pro1619Pro	synonymous	Exon 19 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.4725C>T	p.Pro1575Pro	synonymous	Exon 19 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.4857C>T	p.Pro1619Pro	synonymous	Exon 19 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4857C>T	p.Pro1619Pro	synonymous	Exon 19 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 307 AN: 113410 Hom.: 3 Cov.: 26

Gnomad AFR AF: 0.000767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00433

Gnomad OTH AF: 0.00324

GnomAD2 exomes AF: 0.00279 AC: 493 AN: 176758 AF XY: 0.00268

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00313

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00394 AC: 4310 AN: 1094265 Hom.: 7 Cov.: 32 AF XY: 0.00388 AC XY: 1399 AN XY: 360513

African (AFR) AF: 0.000645 AC: 17 AN: 26349

American (AMR) AF: 0.00122 AC: 43 AN: 35116

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 46 AN: 19309

East Asian (EAS) AF: 0.00 AC: 0 AN: 30116

South Asian (SAS) AF: 0.000686 AC: 37 AN: 53965

European-Finnish (FIN) AF: 0.00286 AC: 113 AN: 39540

Middle Eastern (MID) AF: 0.000971 AC: 4 AN: 4121

European-Non Finnish (NFE) AF: 0.00466 AC: 3914 AN: 839827

Other (OTH) AF: 0.00296 AC: 136 AN: 45922

GnomAD4 genome AF: 0.00271 AC: 307 AN: 113465 Hom.: 3 Cov.: 26 AF XY: 0.00219 AC XY: 78 AN XY: 35603

African (AFR) AF: 0.000766 AC: 24 AN: 31342

American (AMR) AF: 0.00129 AC: 14 AN: 10887

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 5 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.00 AC: 0 AN: 2792

European-Finnish (FIN) AF: 0.00438 AC: 28 AN: 6399

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00433 AC: 231 AN: 53318

Other (OTH) AF: 0.00321 AC: 5 AN: 1560

Alfa AF: 0.00349 Hom.: 27

Bravo AF: 0.00228

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		0.0020
Mutation Taster		=100/0	polymorphism (auto)

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: rs192386572; hg19: chrX-153218182;