NM_005334.3:c.2691G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_005334.3(HCFC1):​c.2691G>A​(p.Ala897Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,210,831 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 25)
Exomes 𝑓: 0.000048 ( 0 hom. 16 hem. )

Consequence

HCFC1
NM_005334.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.86

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant X-153956356-C-T is Benign according to our data. Variant chrX-153956356-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211131.
BP7
Synonymous conserved (PhyloP=-2.86 with no splicing effect.
BS2
High Hemizygotes in GnomAdExome4 at 16 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HCFC1NM_005334.3 linkc.2691G>A p.Ala897Ala synonymous_variant Exon 16 of 26 ENST00000310441.12 NP_005325.2 P51610-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HCFC1ENST00000310441.12 linkc.2691G>A p.Ala897Ala synonymous_variant Exon 16 of 26 1 NM_005334.3 ENSP00000309555.7 P51610-1
HCFC1ENST00000369984.4 linkc.2691G>A p.Ala897Ala synonymous_variant Exon 16 of 26 5 ENSP00000359001.4 A6NEM2

Frequencies

GnomAD3 genomes
AF:
0.0000177
AC:
2
AN:
112973
Hom.:
0
Cov.:
25
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000375
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000441
AC:
8
AN:
181250
AF XY:
0.0000297
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000738
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000863
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000483
AC:
53
AN:
1097858
Hom.:
0
Cov.:
32
AF XY:
0.0000440
AC XY:
16
AN XY:
363284
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26400
American (AMR)
AF:
0.00
AC:
0
AN:
35203
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.0000331
AC:
1
AN:
30205
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54138
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40353
Middle Eastern (MID)
AF:
0.000242
AC:
1
AN:
4128
European-Non Finnish (NFE)
AF:
0.0000582
AC:
49
AN:
841959
Other (OTH)
AF:
0.0000434
AC:
2
AN:
46088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000177
AC:
2
AN:
112973
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
35125
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31107
American (AMR)
AF:
0.00
AC:
0
AN:
10792
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2653
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3610
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2791
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6306
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.0000375
AC:
2
AN:
53268
Other (OTH)
AF:
0.00
AC:
0
AN:
1523
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000264
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2014
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Methylmalonic acidemia with homocystinuria, type cblX Benign:1
Mar 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
0.080
DANN
Benign
0.57
PhyloP100
-2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs374223163; hg19: chrX-153221807; API