X-153954909-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005334.3(HCFC1):c.3490T>A(p.Ser1164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,058,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1164P) has been classified as Benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000028 ( 0 hom. 1 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.650

Publications

30 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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055877656).

BP6

Variant X-153954909-A-T is Benign according to our data. Variant chrX-153954909-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3008076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCFC1	NM_005334.3 link	c.3490T>A	p.Ser1164Thr	missense_variant	Exon 17 of 26	ENST00000310441.12	NP_005325.2	P51610-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12 link	c.3490T>A	p.Ser1164Thr	missense_variant	Exon 17 of 26	1	NM_005334.3	ENSP00000309555.7		P51610-1
HCFC1	ENST00000369984.4 link	c.3490T>A	p.Ser1164Thr	missense_variant	Exon 17 of 26	5		ENSP00000359001.4		A6NEM2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000825

AC:

AN:

121239

AF XY:

0.00

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:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1058798

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

341922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25710

American (AMR)

AF:

0.00

AC:

AN:

30347

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18630

East Asian (EAS)

AF:

0.00

AC:

AN:

28717

South Asian (SAS)

AF:

0.00

AC:

AN:

50970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3339

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

825351

Other (OTH)

AF:

0.00

AC:

AN:

44695

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Aug 29, 2023

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

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.91

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.077

T;T

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.41

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.65

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.025

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.0010

B;.

Vest4

0.083

MutPred

0.16

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.24

MPC

0.50

ClinPred

0.061

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.19

gMVP

0.31

Mutation Taster

=88/12

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over