NM_005334.3:c.4497+138C>G

Variant names:

• chrX-153953469-G-C
• rs762653
• NM_005334.3:c.4497+138C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005334.3(HCFC1):​c.4497+138C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 473,325 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000021 (0 hom. 0 hem.)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.4497+138C>G		intron	N/A	NP_005325.2
	HCFC1	NM_001440843.1		c.4497+138C>G		intron	N/A	NP_001427772.1
	HCFC1	NM_001410705.1		c.4497+138C>G		intron	N/A	NP_001397634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4497+138C>G		intron	N/A	ENSP00000309555.7
	HCFC1	ENST00000925202.1		c.4497+138C>G		intron	N/A	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4497+138C>G		intron	N/A	ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000211 AC: 1 AN: 473325 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131911

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12941

American (AMR) AF: 0.00 AC: 0 AN: 18600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10969

East Asian (EAS) AF: 0.00 AC: 0 AN: 25290

South Asian (SAS) AF: 0.00 AC: 0 AN: 29809

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1557

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 326092

Other (OTH) AF: 0.0000410 AC: 1 AN: 24369

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 382

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-0.088

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: rs762653; hg19: chrX-153218920;