rs371163886

Variant names:

• chrX-153964110-G-C
• rs371163886
• NM_005334.3:c.503+14C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005334.3(HCFC1):​c.503+14C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,185,008 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 363 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., 12 hem., cov: 24)
  • Exomes 𝑓: 0.0010 (0 hom. 351 hem.)
• Consequence: HCFC1 NM_005334.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.50
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-153964110-G-C is Benign according to our data. Variant chrX-153964110-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.503+14C>G		intron	N/A	NP_005325.2
	HCFC1	NM_001440843.1		c.503+14C>G		intron	N/A	NP_001427772.1
	HCFC1	NM_001410705.1		c.503+14C>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.503+14C>G		intron	N/A	ENSP00000309555.7
	HCFC1	ENST00000369984.4	TSL:5	c.503+14C>G		intron	N/A	ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.000676 AC: 76 AN: 112448 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.000754

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000486

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000657

GnomAD2 exomes AF: 0.000836 AC: 135 AN: 161534 AF XY: 0.000858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000861

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000994

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00101 AC: 1083 AN: 1072508 Hom.: 0 Cov.: 29 AF XY: 0.00102 AC XY: 351 AN XY: 343240

African (AFR) AF: 0.0000388 AC: 1 AN: 25773

American (AMR) AF: 0.000718 AC: 24 AN: 33444

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 56 AN: 18417

East Asian (EAS) AF: 0.00 AC: 0 AN: 29560

South Asian (SAS) AF: 0.00 AC: 0 AN: 50926

European-Finnish (FIN) AF: 0.000774 AC: 31 AN: 40039

Middle Eastern (MID) AF: 0.000248 AC: 1 AN: 4040

European-Non Finnish (NFE) AF: 0.00111 AC: 912 AN: 825314

Other (OTH) AF: 0.00129 AC: 58 AN: 44995

GnomAD4 genome AF: 0.000676 AC: 76 AN: 112500 Hom.: 0 Cov.: 24 AF XY: 0.000346 AC XY: 12 AN XY: 34670

African (AFR) AF: 0.0000645 AC: 2 AN: 31019

American (AMR) AF: 0.000280 AC: 3 AN: 10702

Ashkenazi Jewish (ASJ) AF: 0.000754 AC: 2 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2726

European-Finnish (FIN) AF: 0.000486 AC: 3 AN: 6179

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00122 AC: 65 AN: 53200

Other (OTH) AF: 0.000649 AC: 1 AN: 1541

Alfa AF: 0.00113 Hom.: 7

Bravo AF: 0.000589

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.81
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	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: rs371163886; hg19: chrX-153229561;