NM_005334.3:c.344C>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_005334.3(HCFC1):​c.344C>T​(p.Ala115Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). 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)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HCFC1 NM_005334.3 missense, splice_region
• Scores: Splicing: ADA: 0.8887
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• 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: 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant X-153964283-G-A is Pathogenic according to our data. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCFC1	NM_005334.3	MANE Select	c.344C>T	p.Ala115Val	missense splice_region	Exon 3 of 26	NP_005325.2	P51610-1
	HCFC1	NM_001440843.1		c.344C>T	p.Ala115Val	missense splice_region	Exon 3 of 26	NP_001427772.1
	HCFC1	NM_001410705.1		c.344C>T	p.Ala115Val	missense splice_region	Exon 3 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.344C>T	p.Ala115Val	missense splice_region	Exon 3 of 26	ENSP00000309555.7	P51610-1
	HCFC1	ENST00000925202.1		c.344C>T	p.Ala115Val	missense splice_region	Exon 3 of 26	ENSP00000595261.1
	HCFC1	ENST00000369984.4	TSL:5	c.344C>T	p.Ala115Val	missense splice_region	Exon 3 of 26	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1059455 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 335791

African (AFR) AF: 0.00 AC: 0 AN: 25232

American (AMR) AF: 0.00 AC: 0 AN: 31643

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17681

East Asian (EAS) AF: 0.00 AC: 0 AN: 29127

South Asian (SAS) AF: 0.00 AC: 0 AN: 48662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819292

Other (OTH) AF: 0.00 AC: 0 AN: 44356

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Methylmalonic acidemia with homocystinuria, type cblX (4)
-	-	-	Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0021	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		10
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.29		Gain of MoRF binding (P = 0.1104)
MVP		0.78
MPC		3.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.86
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.080		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; COSMIC: COSV107391886; COSMIC: COSV107391886;