rs201404751

Variant names:

• chrX-153955109-T-G
• rs201404751
• NM_005334.3:c.3290A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005334.3(HCFC1):​c.3290A>C​(p.Asn1097Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,202,712 control chromosomes in the GnomAD database, including 1 homozygotes. There are 228 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00056 (0 hom. 208 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.155
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044583976).
• BP6: Variant X-153955109-T-G is Benign according to our data. Variant chrX-153955109-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129220.
• BS2: High Hemizygotes in GnomAd4 at 20 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.3290A>C	p.Asn1097Thr	missense	Exon 17 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.3290A>C	p.Asn1097Thr	missense	Exon 17 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.3290A>C	p.Asn1097Thr	missense	Exon 17 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.3290A>C	p.Asn1097Thr	missense	Exon 17 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.3290A>C	p.Asn1097Thr	missense	Exon 17 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.3290A>C	p.Asn1097Thr	missense	Exon 17 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes AF: 0.000850 AC: 90 AN: 105837 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.0000353

Gnomad AMI AF: 0.0697

Gnomad AMR AF: 0.0000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000800

Gnomad OTH AF: 0.00137

GnomAD2 exomes AF: 0.000373 AC: 67 AN: 179676 AF XY: 0.000377

Gnomad AFR exome AF: 0.0000812

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000624

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000561 AC: 615 AN: 1096875 Hom.: 0 Cov.: 34 AF XY: 0.000574 AC XY: 208 AN XY: 362485

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.000399 AC: 14 AN: 35048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 53939

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40371

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.000682 AC: 574 AN: 841542

Other (OTH) AF: 0.000586 AC: 27 AN: 46050

GnomAD4 genome AF: 0.000850 AC: 90 AN: 105837 Hom.: 1 Cov.: 24 AF XY: 0.000658 AC XY: 20 AN XY: 30399

African (AFR) AF: 0.0000353 AC: 1 AN: 28320

American (AMR) AF: 0.0000982 AC: 1 AN: 10186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2563

East Asian (EAS) AF: 0.00 AC: 0 AN: 3237

South Asian (SAS) AF: 0.00 AC: 0 AN: 2364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.000800 AC: 41 AN: 51252

Other (OTH) AF: 0.00137 AC: 2 AN: 1456

Alfa AF: 0.000629 Hom.: 25

Bravo AF: 0.00101

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.00120 AC: 8

ExAC AF: 0.000297 AC: 36

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	HCFC1-related disorder (1)
-	-	1	Methylmalonic acidemia with homocystinuria, type cblX (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.15
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.043
Sift	Benign	0.050	D
Sift4G	Benign	0.42	T
Polyphen		0.0040	B
Vest4		0.13
MVP		0.36
MPC		0.57
ClinPred		0.0094	T
GERP RS		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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: rs201404751; hg19: chrX-153220560; COSMIC: COSV108122610; COSMIC: COSV108122610;