rs782652831

Variant names:

• chrX-153952880-C-T
• rs782652831
• NM_005334.3:c.4576G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005334.3(HCFC1):​c.4576G>A​(p.Ala1526Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,068,384 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000056 (0 hom. 1 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.313
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04735458).

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.4576G>A	p.Ala1526Thr	missense	Exon 19 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.4708G>A	p.Ala1570Thr	missense	Exon 19 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.4708G>A	p.Ala1570Thr	missense	Exon 19 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.4576G>A	p.Ala1526Thr	missense	Exon 19 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.4708G>A	p.Ala1570Thr	missense	Exon 19 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.4708G>A	p.Ala1570Thr	missense	Exon 19 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.0000310 AC: 4 AN: 129034 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000562 AC: 6 AN: 1068384 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 1 AN XY: 346840

African (AFR) AF: 0.00 AC: 0 AN: 25676

American (AMR) AF: 0.000194 AC: 6 AN: 30918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18928

East Asian (EAS) AF: 0.00 AC: 0 AN: 28427

South Asian (SAS) AF: 0.00 AC: 0 AN: 51310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828410

Other (OTH) AF: 0.00 AC: 0 AN: 45027

GnomAD4 genome Cov.: 26

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000260 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.31
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.058
Sift	Benign	0.080	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.11		Gain of glycosylation at A1526 (P = 0.0325)
MVP		0.21
MPC		0.53
ClinPred		0.031	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.39
Mutation Taster		=97/3	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: rs782652831; hg19: chrX-153218331;