rs782011168

Variant names:

• chrX-153949394-G-A
• rs782011168
• NM_005334.3:c.6069-8C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005334.3(HCFC1):​c.6069-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,201,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: HCFC1 NM_005334.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003096
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.396
• 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: Ambry Genetics, Orphanet, G2P, 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-153949394-G-A is Benign according to our data. Variant chrX-153949394-G-A is described in ClinVar as Benign. ClinVar VariationId is 2883031.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.6069-8C>T		splice_region intron	N/A	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.6210-8C>T		splice_region intron	N/A	NP_001427772.1
	HCFC1	NM_001410705.1		c.6204-8C>T		splice_region intron	N/A	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.6069-8C>T		splice_region intron	N/A	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.6210-8C>T		splice_region intron	N/A	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.6204-8C>T		splice_region intron	N/A	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 110986 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000445 AC: 8 AN: 179643 AF XY: 0.0000455

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1090466 Hom.: 0 Cov.: 29 AF XY: 0.0000112 AC XY: 4 AN XY: 356410

African (AFR) AF: 0.00 AC: 0 AN: 26226

American (AMR) AF: 0.00 AC: 0 AN: 34986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19291

East Asian (EAS) AF: 0.000431 AC: 13 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835951

Other (OTH) AF: 0.00 AC: 0 AN: 45797

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 110986 Hom.: 0 Cov.: 23 AF XY: 0.0000603 AC XY: 2 AN XY: 33174

African (AFR) AF: 0.00 AC: 0 AN: 30423

American (AMR) AF: 0.00 AC: 0 AN: 10586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2605

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5959

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52825

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.010
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: rs782011168; hg19: chrX-153214845;