rs397515487

Variant names:

• chrX-153964703-C-T
• rs397515487
• NM_005334.3:c.217G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_005334.3(HCFC1):​c.217G>A​(p.Ala73Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A73V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.70
• Publications: 3 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 5 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-153964702-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66985.
• PP5: Variant X-153964703-C-T is Pathogenic according to our data. Variant chrX-153964703-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 66986.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.217G>A	p.Ala73Thr	missense_variant	Exon 2 of 26	5		ENSP00000359001.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Pathogenic:1

Sep 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Disorders of Intracellular Cobalamin Metabolism Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.025	D;D
Vest4		0.56
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.63
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs397515487; hg19: chrX-153230154;