rs1053320929

Variant names:

• chrX-153954934-C-T
• rs1053320929
• NM_005334.3:c.3465G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_005334.3(HCFC1):​c.3465G>A​(p.Ala1155Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,074,850 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000074 (0 hom. 1 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.429
• 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: G2P, Ambry Genetics, Orphanet, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-153954934-C-T is Benign according to our data. Variant chrX-153954934-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 435398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.429 with no splicing effect.

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.3465G>A	p.Ala1155Ala	synonymous	Exon 17 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.3465G>A	p.Ala1155Ala	synonymous	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.3465G>A	p.Ala1155Ala	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.3465G>A	p.Ala1155Ala	synonymous	Exon 17 of 26	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.3465G>A	p.Ala1155Ala	synonymous	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.3465G>A	p.Ala1155Ala	synonymous	Exon 17 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142622 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000744 AC: 8 AN: 1074850 Hom.: 0 Cov.: 34 AF XY: 0.00000287 AC XY: 1 AN XY: 348836

African (AFR) AF: 0.00 AC: 0 AN: 26043

American (AMR) AF: 0.00 AC: 0 AN: 32974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18952

East Asian (EAS) AF: 0.00 AC: 0 AN: 29454

South Asian (SAS) AF: 0.00 AC: 0 AN: 52165

European-Finnish (FIN) AF: 0.0000296 AC: 1 AN: 33830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3547

European-Non Finnish (NFE) AF: 0.00000841 AC: 7 AN: 832612

Other (OTH) AF: 0.00 AC: 0 AN: 45273

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.78
CADD	Benign	0.28
DANN	Benign	0.46
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs1053320929; hg19: chrX-153220385;