rs782063013

Variant names:

• chrX-153951350-G-A
• rs782063013
• NM_005334.3:c.5517C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005334.3(HCFC1):​c.5517C>T​(p.Asp1839Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,209,492 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 2 hem., cov: 25)
  • Exomes 𝑓: 0.000067 (0 hom. 43 hem.)
• Consequence: HCFC1 NM_005334.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002391
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.916
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-153951350-G-A is Benign according to our data. Variant chrX-153951350-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.916 with no splicing effect.
• BS2: High Hemizygotes 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.5517C>T	p.Asp1839Asp	splice_region synonymous	Exon 22 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.5658C>T	p.Asp1886Asp	splice_region synonymous	Exon 22 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.5652C>T	p.Asp1884Asp	splice_region synonymous	Exon 22 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.5517C>T	p.Asp1839Asp	splice_region synonymous	Exon 22 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.5658C>T	p.Asp1886Asp	splice_region synonymous	Exon 22 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.5652C>T	p.Asp1884Asp	splice_region synonymous	Exon 22 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.0000626 AC: 7 AN: 111838 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 26 AN: 181393 AF XY: 0.000208

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: 0.0000629

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000674 AC: 74 AN: 1097602 Hom.: 0 Cov.: 31 AF XY: 0.000118 AC XY: 43 AN XY: 363034

African (AFR) AF: 0.0000379 AC: 1 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00124 AC: 67 AN: 54122

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841752

Other (OTH) AF: 0.00 AC: 0 AN: 46067

GnomAD4 genome AF: 0.0000626 AC: 7 AN: 111890 Hom.: 0 Cov.: 25 AF XY: 0.0000587 AC XY: 2 AN XY: 34060

African (AFR) AF: 0.00 AC: 0 AN: 30853

American (AMR) AF: 0.00 AC: 0 AN: 10625

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00188 AC: 5 AN: 2666

European-Finnish (FIN) AF: 0.000330 AC: 2 AN: 6055

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53044

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.0000508 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	-0.79
CADD	Benign	0.095
DANN	Benign	0.54
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.010		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: rs782063013; hg19: chrX-153216801;