Genetic Variant HCFC1:p.Pro947Pro (chrX-153956206-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001440843.1(HCFC1):c.2841A>G(p.Pro947Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,208,505 control chromosomes in the GnomAD database, including 39,227 homozygotes. There are 104,147 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 8046 hom., 13261 hem., cov: 25)

Exomes 𝑓: 0.24 ( 31181 hom. 90886 hem. )

Consequence

HCFC1
NM_001440843.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.213

Publications

12 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant X-153956206-T-C is Benign according to our data. Variant chrX-153956206-T-C is described in ClinVar as Benign. ClinVar VariationId is 95277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.213 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

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.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	NP_005325.2
HCFC1	NM_001440843.1		c.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	NP_001397634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	ENSP00000309555.7
HCFC1	ENST00000925202.1		c.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	ENSP00000595261.1
HCFC1	ENST00000369984.4	TSL:5	c.2841A>G	p.Pro947Pro	synonymous	Exon 16 of 26	ENSP00000359001.4

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

43008

AN:

112313

Hom.:

8037

Cov.:

show subpopulations

Gnomad AFR

AF:

0.688

Gnomad AMI

AF:

0.0675

Gnomad AMR

AF:

0.496

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.761

Gnomad SAS

AF:

0.597

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.359

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.407

GnomAD2 exomes

AF:

0.376

AC:

67963

AN:

180824

AF XY:

0.357

show subpopulations

Gnomad AFR exome

AF:

0.700

Gnomad AMR exome

AF:

0.624

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.763

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.178

Gnomad OTH exome

AF:

0.331

GnomAD4 exome

AF:

0.243

AC:

265917

AN:

1096138

Hom.:

31181

Cov.:

AF XY:

0.251

AC XY:

90886

AN XY:

362000

show subpopulations

African (AFR)

AF:

0.699

AC:

18428

AN:

26364

American (AMR)

AF:

0.610

AC:

21435

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

5554

AN:

19369

East Asian (EAS)

AF:

0.749

AC:

22625

AN:

30189

South Asian (SAS)

AF:

0.572

AC:

30917

AN:

54079

European-Finnish (FIN)

AF:

0.179

AC:

7208

AN:

40316

Middle Eastern (MID)

AF:

0.409

AC:

1509

AN:

3691

European-Non Finnish (NFE)

AF:

0.171

AC:

144006

AN:

840986

Other (OTH)

AF:

0.309

AC:

14235

AN:

45995

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

6246

12491

18737

24982

31228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5972

11944

17916

23888

29860

<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:

0.383

AC:

43067

AN:

112367

Hom.:

8046

Cov.:

AF XY:

0.384

AC XY:

13261

AN XY:

34563

show subpopulations

African (AFR)

AF:

0.688

AC:

21258

AN:

30905

American (AMR)

AF:

0.497

AC:

5339

AN:

10743

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

682

AN:

2650

East Asian (EAS)

AF:

0.761

AC:

2679

AN:

3522

South Asian (SAS)

AF:

0.594

AC:

1629

AN:

2742

European-Finnish (FIN)

AF:

0.178

AC:

1112

AN:

6237

Middle Eastern (MID)

AF:

0.366

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.181

AC:

9609

AN:

53147

Other (OTH)

AF:

0.416

AC:

634

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

721

1442

2163

2884

3605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<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:

0.246

Hom.:

4822

Bravo

AF:

0.425

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Methylmalonic acidemia with homocystinuria, type cblX (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.9

(source)

DANN

Benign

0.22

PhyloP100

-0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=95/5

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

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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