rs17421

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005334.3(HCFC1):c.1085-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,198,814 control chromosomes in the GnomAD database, including 26,825 homozygotes. There are 89,093 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.21 ( 2561 hom., 7303 hem., cov: 23)

Exomes 𝑓: 0.22 ( 24264 hom. 81790 hem. )

Consequence

HCFC1
NM_005334.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.602

Publications

7 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-153960183-G-C is Benign according to our data. Variant chrX-153960183-G-C is described in ClinVar as Benign. ClinVar VariationId is 676217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
HCFC1	NM_005334.3	MANE Select	c.1085-22C>G	intron	N/A	NP_005325.2	P51610-1
HCFC1	NM_001440843.1		c.1085-22C>G	intron	N/A	NP_001427772.1
HCFC1	NM_001410705.1		c.1085-22C>G	intron	N/A	NP_001397634.1	A6NEM2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.1085-22C>G	intron	N/A	ENSP00000309555.7	P51610-1
HCFC1	ENST00000925202.1		c.1085-22C>G	intron	N/A	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.1085-22C>G	intron	N/A	ENSP00000359001.4	A6NEM2

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

23304

AN:

111117

Hom.:

2554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.0706

Gnomad AMR

AF:

0.421

Gnomad ASJ

AF:

0.253

Gnomad EAS

AF:

0.755

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.295

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.254

GnomAD2 exomes

AF:

0.329

AC:

53031

AN:

161178

AF XY:

0.328

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.589

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.761

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.305

GnomAD4 exome

AF:

0.218

AC:

236855

AN:

1087643

Hom.:

24264

Cov.:

AF XY:

0.231

AC XY:

81790

AN XY:

354713

show subpopulations

African (AFR)

AF:

0.112

AC:

2939

AN:

26282

American (AMR)

AF:

0.571

AC:

19517

AN:

34165

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

5452

AN:

19066

East Asian (EAS)

AF:

0.752

AC:

22531

AN:

29968

South Asian (SAS)

AF:

0.571

AC:

30278

AN:

53043

European-Finnish (FIN)

AF:

0.176

AC:

7015

AN:

39952

Middle Eastern (MID)

AF:

0.381

AC:

1554

AN:

4077

European-Non Finnish (NFE)

AF:

0.162

AC:

135640

AN:

835423

Other (OTH)

AF:

0.261

AC:

11929

AN:

45667

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6212

12424

18636

24848

31060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5526

11052

16578

22104

27630

<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:

0.210

AC:

23319

AN:

111171

Hom.:

2561

Cov.:

AF XY:

0.219

AC XY:

7303

AN XY:

33403

show subpopulations

African (AFR)

AF:

0.114

AC:

3507

AN:

30645

American (AMR)

AF:

0.422

AC:

4437

AN:

10515

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

663

AN:

2622

East Asian (EAS)

AF:

0.755

AC:

2638

AN:

3494

South Asian (SAS)

AF:

0.591

AC:

1527

AN:

2585

European-Finnish (FIN)

AF:

0.166

AC:

991

AN:

5979

Middle Eastern (MID)

AF:

0.300

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.171

AC:

9040

AN:

52918

Other (OTH)

AF:

0.266

AC:

404

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

571

1142

1714

2285

2856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.209

Hom.:

1896

Bravo

AF:

0.230

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Methylmalonic acidemia with homocystinuria, type cblX (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.1

(source)

DANN

Benign

0.72

PhyloP100

-0.60

BranchPoint Hunter

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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