rs3027888

Variant names:

• chrX-153957806-C-T
• rs3027888
• NM_005334.3:c.2109G>A

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.2109G>A​(p.Thr703Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,205,510 control chromosomes in the GnomAD database, including 27 homozygotes. There are 2,678 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 0.0048 (2 hom., 122 hem., cov: 24)
  • Exomes 𝑓: 0.0070 (25 hom. 2556 hem.)
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.32
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-153957806-C-T is Benign according to our data. Variant chrX-153957806-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BS2: High Homozygotes 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.2109G>A	p.Thr703Thr	synonymous	Exon 12 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.2109G>A	p.Thr703Thr	synonymous	Exon 12 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.2109G>A	p.Thr703Thr	synonymous	Exon 12 of 26	NP_001397634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.2109G>A	p.Thr703Thr	synonymous	Exon 12 of 26	ENSP00000309555.7
	HCFC1	ENST00000369984.4	TSL:5	c.2109G>A	p.Thr703Thr	synonymous	Exon 12 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 543 AN: 112222 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.000615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00859

Gnomad FIN AF: 0.000643

Gnomad MID AF: 0.0335

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00729

GnomAD2 exomes AF: 0.00582 AC: 1056 AN: 181479 AF XY: 0.00667

Gnomad AFR exome AF: 0.000484

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000943

Gnomad NFE exome AF: 0.00790

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00695 AC: 7599 AN: 1093235 Hom.: 25 Cov.: 30 AF XY: 0.00712 AC XY: 2556 AN XY: 358887

African (AFR) AF: 0.000418 AC: 11 AN: 26298

American (AMR) AF: 0.00185 AC: 65 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 388 AN: 19355

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00878 AC: 474 AN: 54008

European-Finnish (FIN) AF: 0.00114 AC: 46 AN: 40455

Middle Eastern (MID) AF: 0.0182 AC: 75 AN: 4125

European-Non Finnish (NFE) AF: 0.00746 AC: 6251 AN: 837674

Other (OTH) AF: 0.00629 AC: 289 AN: 45934

GnomAD4 genome AF: 0.00480 AC: 539 AN: 112275 Hom.: 2 Cov.: 24 AF XY: 0.00354 AC XY: 122 AN XY: 34447

African (AFR) AF: 0.000614 AC: 19 AN: 30939

American (AMR) AF: 0.00187 AC: 20 AN: 10716

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 58 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00824 AC: 22 AN: 2670

European-Finnish (FIN) AF: 0.000643 AC: 4 AN: 6220

Middle Eastern (MID) AF: 0.0229 AC: 5 AN: 218

European-Non Finnish (NFE) AF: 0.00754 AC: 400 AN: 53078

Other (OTH) AF: 0.00719 AC: 11 AN: 1529

Alfa AF: 0.00891 Hom.: 78

Bravo AF: 0.00435

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Methylmalonic acidemia with homocystinuria, type cblX (2)
-	-	1	HCFC1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.27
DANN	Benign	0.63
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=93/7	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: rs3027888; hg19: chrX-153223257;