rs1557112939

Variant names:

• chrX-153952697-G-A
• rs1557112939
• NM_005334.3:c.4759C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153952697-G-A
• chrX-153952697-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005334.3(HCFC1):​c.4759C>T​(p.Leu1587Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,095,598 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: HCFC1 NM_005334.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26
• 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: 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24863142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3	c.4759C>T	p.Leu1587Phe	missense_variant	Exon 19 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12	c.4759C>T	p.Leu1587Phe	missense_variant	Exon 19 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4	c.4891C>T	p.Leu1631Phe	missense_variant	Exon 19 of 26	5		ENSP00000359001.4
HCFC1	ENST00000444191.5	c.481C>T	p.Leu161Phe	missense_variant	Exon 3 of 10	5		ENSP00000399589.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095598 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361674

African (AFR) AF: 0.00 AC: 0 AN: 26368

American (AMR) AF: 0.00 AC: 0 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.00 AC: 0 AN: 53920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39617

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841005

Other (OTH) AF: 0.00 AC: 0 AN: 45997

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 24, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		5.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.0090	B;.
Vest4		0.28
MutPred		0.19		Gain of catalytic residue at M1592 (P = 0.0394);.;
MVP		0.61
MPC		1.5
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.73
gMVP		0.81
Mutation Taster		=76/24	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: rs1557112939; hg19: chrX-153218148;