NM_005334.3:c.4442C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005334.3(HCFC1):c.4442C>T(p.Thr1481Met) variant causes a missense change. The variant allele was found at a frequency of 0.000354 in 1,209,424 control chromosomes in the GnomAD database, including 1 homozygotes. There are 136 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1481T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., 15 hem., cov: 24)

Exomes 𝑓: 0.00036 ( 1 hom. 121 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.17

Publications

5 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006960392).

BP6

Variant X-153953662-G-A is Benign according to our data. Variant chrX-153953662-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 15 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005334.3. 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.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	NP_005325.2
HCFC1	NM_001440843.1		c.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	NP_001397634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	ENSP00000309555.7
HCFC1	ENST00000925202.1		c.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.4442C>T	p.Thr1481Met	missense	Exon 18 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

112430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000928

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00813

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.000662

GnomAD2 exomes

AF:

0.00115

AC:

207

AN:

180011

AF XY:

0.000973

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000356

AC:

391

AN:

1096944

Hom.:

Cov.:

AF XY:

0.000334

AC XY:

121

AN XY:

362740

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26393

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.0107

AC:

322

AN:

30199

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39721

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.0000535

AC:

AN:

841744

Other (OTH)

AF:

0.000413

AC:

AN:

46055

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

113

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:

0.000329

AC:

AN:

112480

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

AN XY:

34638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30997

American (AMR)

AF:

0.0000927

AC:

AN:

10784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00816

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6261

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53136

Other (OTH)

AF:

0.000654

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000869

Hom.:

Bravo

AF:

0.000638

ExAC

AF:

0.000891

AC:

108

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

HCFC1-related disorder (1)

Methylmalonic acidemia with homocystinuria, type cblX (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

4.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

REVEL

Benign

0.12

Sift

Uncertain

0.015

Sift4G

Benign

0.073

Polyphen

0.92

Vest4

0.20

MVP

0.45

MPC

0.71

ClinPred

0.050

GERP RS

5.9

PromoterAI

-0.047

Neutral

(source)

Varity_R

0.10

gMVP

0.37

Mutation Taster

=94/6

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over