rs372900932

Variant names:

• chrX-153952830-C-T
• rs372900932
• NM_005334.3:c.4626G>A

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.4626G>A​(p.Glu1542Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,193,314 control chromosomes in the GnomAD database, including 7 homozygotes. There are 27 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 0.00011 (2 hom., 2 hem., cov: 26)
  • Exomes 𝑓: 0.000086 (5 hom. 25 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.629
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.048).
• BP6: Variant X-153952830-C-T is Benign according to our data. Variant chrX-153952830-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.629 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 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.4626G>A	p.Glu1542Glu	synonymous	Exon 19 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.4758G>A	p.Glu1586Glu	synonymous	Exon 19 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4758G>A	p.Glu1586Glu	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.4626G>A	p.Glu1542Glu	synonymous	Exon 19 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.4758G>A	p.Glu1586Glu	synonymous	Exon 19 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4758G>A	p.Glu1586Glu	synonymous	Exon 19 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 12 AN: 112906 Hom.: 2 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000927

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00277

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000658

GnomAD2 exomes AF: 0.000143 AC: 21 AN: 146517 AF XY: 0.000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000263

GnomAD4 exome AF: 0.0000861 AC: 93 AN: 1080354 Hom.: 5 Cov.: 32 AF XY: 0.0000714 AC XY: 25 AN XY: 350348

African (AFR) AF: 0.00 AC: 0 AN: 26048

American (AMR) AF: 0.0000601 AC: 2 AN: 33293

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19031

East Asian (EAS) AF: 0.00102 AC: 30 AN: 29419

South Asian (SAS) AF: 0.0000382 AC: 2 AN: 52393

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833557

Other (OTH) AF: 0.00130 AC: 59 AN: 45439

GnomAD4 genome AF: 0.000106 AC: 12 AN: 112960 Hom.: 2 Cov.: 26 AF XY: 0.0000570 AC XY: 2 AN XY: 35110

African (AFR) AF: 0.00 AC: 0 AN: 31172

American (AMR) AF: 0.0000926 AC: 1 AN: 10796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00278 AC: 10 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6299

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53277

Other (OTH) AF: 0.000650 AC: 1 AN: 1538

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.0
DANN	Benign	0.48
PhyloP100		0.63
Mutation Taster		=95/5	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: rs372900932; hg19: chrX-153218281;