chrX-153950915-G-A

Variant names:

• chrX-153950915-G-A
• rs144160012
• NM_005334.3:c.5601C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005334.3(HCFC1):​c.5601C>T​(p.Ala1867Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,209,367 control chromosomes in the GnomAD database, including 14 homozygotes. There are 453 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1867A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 51 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (13 hom. 402 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.62
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.026).
• BP6: Variant X-153950915-G-A is Benign according to our data. Variant chrX-153950915-G-A is described in ClinVar as Benign. ClinVar VariationId is 506490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00115 (130/112622) while in subpopulation EAS AF = 0.0325 (116/3571). AF 95% confidence interval is 0.0277. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 51 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.5601C>T	p.Ala1867Ala	synonymous	Exon 23 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.5742C>T	p.Ala1914Ala	synonymous	Exon 23 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.5736C>T	p.Ala1912Ala	synonymous	Exon 23 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.5601C>T	p.Ala1867Ala	synonymous	Exon 23 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.5742C>T	p.Ala1914Ala	synonymous	Exon 23 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.5736C>T	p.Ala1912Ala	synonymous	Exon 23 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 130 AN: 112570 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000939

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00317 AC: 575 AN: 181600 AF XY: 0.00309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.00107 AC: 1178 AN: 1096745 Hom.: 13 Cov.: 32 AF XY: 0.00111 AC XY: 402 AN XY: 362597

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0317 AC: 958 AN: 30204

South Asian (SAS) AF: 0.00194 AC: 105 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000808 AC: 68 AN: 841483

Other (OTH) AF: 0.000977 AC: 45 AN: 46067

GnomAD4 genome AF: 0.00115 AC: 130 AN: 112622 Hom.: 1 Cov.: 24 AF XY: 0.00147 AC XY: 51 AN XY: 34774

African (AFR) AF: 0.00 AC: 0 AN: 31048

American (AMR) AF: 0.0000933 AC: 1 AN: 10714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.0325 AC: 116 AN: 3571

South Asian (SAS) AF: 0.00291 AC: 8 AN: 2752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53256

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.000207 Hom.: 2

Bravo AF: 0.00197

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.035
DANN	Benign	0.61
PhyloP100		-3.6
Mutation Taster		=98/2	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: rs144160012; hg19: chrX-153216366; COSMIC: COSV60074660;