X-153954909-A-G

Position:

chrX-153954909-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005334.3(HCFC1):c.3490T>C(p.Ser1164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,169,617 control chromosomes in the GnomAD database, including 37,426 homozygotes. There are 97,476 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 7971 hom., 12912 hem., cov: 24)

Exomes 𝑓: 0.24 ( 29455 hom. 84564 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.650

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HCFC1. . Gene score misZ 5.6341 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability, non-syndromic X-linked intellectual disability, methylmalonic acidemia with homocystinuria, type cblX.

BP4

Computational evidence support a benign effect (MetaRNN=1.4520427E-6).

BP6

Variant X-153954909-A-G is Benign according to our data. Variant chrX-153954909-A-G is described in ClinVar as [Benign]. Clinvar id is 95278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153954909-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.3490T>C	p.Ser1164Pro	missense_variant	17/26	ENST00000310441.12	NP_005325.2	P51610-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCFC1	ENST00000310441.12 linkuse as main transcript	c.3490T>C	p.Ser1164Pro	missense_variant	17/26	1	NM_005334.3	ENSP00000309555.7		P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.3490T>C	p.Ser1164Pro	missense_variant	17/26	5		ENSP00000359001.4		A6NEM2

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

42496

AN:

111025

Hom.:

7962

Cov.:

AF XY:

0.386

AC XY:

12865

AN XY:

33317

show subpopulations

Gnomad AFR

AF:

0.686

Gnomad AMI

AF:

0.0682

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.763

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.353

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.407

GnomAD3 exomes

AF:

0.387

AC:

46926

AN:

121239

Hom.:

9248

AF XY:

0.379

AC XY:

12732

AN XY:

33571

show subpopulations

Gnomad AFR exome

AF:

0.699

Gnomad AMR exome

AF:

0.609

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.760

Gnomad SAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

AF:

0.239

AC:

252780

AN:

1058535

Hom.:

29455

Cov.:

AF XY:

0.247

AC XY:

84564

AN XY:

341803

show subpopulations

Gnomad4 AFR exome

AF:

0.694

Gnomad4 AMR exome

AF:

0.598

Gnomad4 ASJ exome

AF:

0.286

Gnomad4 EAS exome

AF:

0.750

Gnomad4 SAS exome

AF:

0.572

Gnomad4 FIN exome

AF:

0.176

Gnomad4 NFE exome

AF:

0.170

Gnomad4 OTH exome

AF:

0.308

GnomAD4 genome

AF:

0.383

AC:

42556

AN:

111082

Hom.:

7971

Cov.:

AF XY:

0.387

AC XY:

12912

AN XY:

33384

show subpopulations

Gnomad4 AFR

AF:

0.687

Gnomad4 AMR

AF:

0.500

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.762

Gnomad4 SAS

AF:

0.607

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.416

Alfa

AF:

0.249

Hom.:

12051

Bravo

AF:

0.423

TwinsUK

AF:

0.175

AC:

650

ALSPAC

AF:

0.174

AC:

503

ESP6500AA

AF:

0.638

AC:

2283

ESP6500EA

AF:

0.180

AC:

1169

ExAC

AF:

0.332

AC:

37527

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2016	- -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

9.5

DANN

Benign

0.13

DEOGEN2

Benign

0.069

T;T

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.048

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.049

MPC

0.69

ClinPred

0.00095

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.11

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over