X-153964283-G-C

Variant names:

• chrX-153964283-G-C
• rs397515485
• NM_005334.3:c.344C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_005334.3(HCFC1):​c.344C>G​(p.Ala115Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A115T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HCFC1 NM_005334.3 missense, splice_region
• Scores: Splicing: ADA: 0.6763
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 6 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153964283-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.344C>G	p.Ala115Gly	missense splice_region	Exon 3 of 26	NP_005325.2
	HCFC1	NM_001440843.1		c.344C>G	p.Ala115Gly	missense splice_region	Exon 3 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.344C>G	p.Ala115Gly	missense splice_region	Exon 3 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.344C>G	p.Ala115Gly	missense splice_region	Exon 3 of 26	ENSP00000309555.7
	HCFC1	ENST00000369984.4	TSL:5	c.344C>G	p.Ala115Gly	missense splice_region	Exon 3 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000668 AC: 1 AN: 149805 AF XY: 0.00

Gnomad AFR exome AF: 0.0000866

Gnomad AMR exome AF: 0.00

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 Cov.: 30

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000497 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		10
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.37		Gain of relative solvent accessibility (P = 0.09)
MVP		0.83
MPC		3.2
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.85
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.040		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: rs397515485; hg19: chrX-153229734;