chrX-153952837-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001440843.1(HCFC1):c.4751C>T(p.Thr1584Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,192,624 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1584S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 26)

Exomes 𝑓: 0.000032 ( 0 hom. 10 hem. )

Consequence

HCFC1
NM_001440843.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0410

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

HCFC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03781441).

BP6

Variant X-153952837-G-A is Benign according to our data. Variant chrX-153952837-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 424226.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440843.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	NM_005334.3	MANE Select	c.4619C>T	p.Thr1540Ile	missense	Exon 19 of 26	NP_005325.2
HCFC1	NM_001440843.1		c.4751C>T	p.Thr1584Ile	missense	Exon 19 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.4751C>T	p.Thr1584Ile	missense	Exon 19 of 26	NP_001397634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4619C>T	p.Thr1540Ile	missense	Exon 19 of 26	ENSP00000309555.7
HCFC1	ENST00000925202.1		c.4751C>T	p.Thr1584Ile	missense	Exon 19 of 26	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.4751C>T	p.Thr1584Ile	missense	Exon 19 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112991

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

144008

AF XY:

0.0000465

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000658

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000324

AC:

AN:

1079633

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

350339

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26017

American (AMR)

AF:

0.0000302

AC:

AN:

33066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19081

East Asian (EAS)

AF:

0.00

AC:

AN:

29337

South Asian (SAS)

AF:

0.00

AC:

AN:

52350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000408

AC:

AN:

833402

Other (OTH)

AF:

0.00

AC:

AN:

45428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

AN:

112991

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

35119

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31130

American (AMR)

AF:

0.0000926

AC:

AN:

10795

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3613

South Asian (SAS)

AF:

0.00

AC:

AN:

2737

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53304

Other (OTH)

AF:

0.00

AC:

AN:

1516

Age Distribution

Genome Hom

Variant carriers

<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.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000253

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic acidemia with homocystinuria, type cblX (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.90

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.80

M_CAP

Benign

0.0077

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

-0.041

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

REVEL

Benign

0.032

Sift

Uncertain

0.0080

Sift4G

Benign

0.072

Polyphen

0.0020

Vest4

0.026

MutPred

0.21

Loss of phosphorylation at T1540 (P = 0.0172)

MVP

0.11

MPC

0.59

ClinPred

0.021

GERP RS

-2.4

Varity_R

0.097

gMVP

0.47

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over