dbSNP rs782665288: HCFC1:p.Ala1532Thr (chrX-153952862-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005334.3(HCFC1):c.4594G>A(p.Ala1532Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A1532A) has been classified as Benign.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.34

Publications

0 publications found

Variant links:

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

HCFC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040997088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.4594G>A	p.Ala1532Thr	missense_variant	Exon 19 of 26	ENST00000310441.12	NP_005325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HCFC1	ENST00000310441.12 link	c.4594G>A	p.Ala1532Thr	missense_variant	Exon 19 of 26	1	NM_005334.3	ENSP00000309555.7
HCFC1	ENST00000369984.4 link	c.4726G>A	p.Ala1576Thr	missense_variant	Exon 19 of 26	5		ENSP00000359001.4
HCFC1	ENST00000444191.5 link	c.316G>A	p.Ala106Thr	missense_variant	Exon 3 of 10	5		ENSP00000399589.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

129138

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1069171

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346331

African (AFR)

AF:

0.00

AC:

AN:

25693

American (AMR)

AF:

0.00

AC:

AN:

31208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18916

East Asian (EAS)

AF:

0.00

AC:

AN:

28592

South Asian (SAS)

AF:

0.00

AC:

AN:

51442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

828654

Other (OTH)

AF:

0.00

AC:

AN:

45045

GnomAD4 genome

Cov.:

Alfa

AF:

0.000999

Hom.:

ExAC

AF:

0.00000859

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.019

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.081

T;T

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;.

PhyloP100

-2.3

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.54

N;N

Sift

Benign

0.55

T;T

Sift4G

Benign

0.11

T;T

Vest4

0.016

ClinPred

0.032

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.042

gMVP

0.43

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over