rs376049260

Variant names:

• chrX-153954907-G-A
• rs376049260
• NM_005334.3:c.3492C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005334.3(HCFC1):​c.3492C>T​(p.Ser1164Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,169,225 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 414 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., 29 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (0 hom. 385 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0830
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-153954907-G-A is Benign according to our data. Variant chrX-153954907-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211134.
• BP7: Synonymous conserved (PhyloP=-0.083 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 29 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.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	NP_001397634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.3492C>T	p.Ser1164Ser	synonymous	Exon 17 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.000792 AC: 89 AN: 112331 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000644

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000666 AC: 80 AN: 120161 AF XY: 0.000710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.000305

GnomAD4 exome AF: 0.00109 AC: 1152 AN: 1056841 Hom.: 0 Cov.: 34 AF XY: 0.00113 AC XY: 385 AN XY: 340155

African (AFR) AF: 0.000157 AC: 4 AN: 25521

American (AMR) AF: 0.00 AC: 0 AN: 29867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18503

East Asian (EAS) AF: 0.00 AC: 0 AN: 28617

South Asian (SAS) AF: 0.0000594 AC: 3 AN: 50474

European-Finnish (FIN) AF: 0.000837 AC: 26 AN: 31067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3362

European-Non Finnish (NFE) AF: 0.00129 AC: 1067 AN: 824821

Other (OTH) AF: 0.00117 AC: 52 AN: 44609

GnomAD4 genome AF: 0.000792 AC: 89 AN: 112384 Hom.: 0 Cov.: 24 AF XY: 0.000839 AC XY: 29 AN XY: 34582

African (AFR) AF: 0.000258 AC: 8 AN: 31030

American (AMR) AF: 0.000184 AC: 2 AN: 10846

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3477

South Asian (SAS) AF: 0.00 AC: 0 AN: 2737

European-Finnish (FIN) AF: 0.000644 AC: 4 AN: 6213

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

European-Non Finnish (NFE) AF: 0.00142 AC: 75 AN: 52997

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.000651 Hom.: 4

Bravo AF: 0.000722

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	1	HCFC1-related disorder (1)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.3
DANN	Benign	0.62
PhyloP100		-0.083
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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: rs376049260; hg19: chrX-153220358;