X-153954605-G-A

Position:

chrX-153954605-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_005334.3(HCFC1):c.3794C>T(p.Ser1265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,208,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 45 hem., cov: 25)

Exomes 𝑓: 0.00090 ( 0 hom. 287 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.67

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 -15 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=0.0054138303).

BP6

Variant X-153954605-G-A is Benign according to our data. Variant chrX-153954605-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 376776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.3794C>T	p.Ser1265Leu	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.3794C>T	p.Ser1265Leu	missense_variant	17/26	1	NM_005334.3	ENSP00000309555.7		P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.3794C>T	p.Ser1265Leu	missense_variant	17/26	5		ENSP00000359001.4		A6NEM2

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

176

AN:

112645

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

34825

show subpopulations

Gnomad AFR

AF:

0.00406

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000645

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000659

Gnomad OTH

AF:

0.00196

GnomAD3 exomes

AF:

0.000736

AC:

130

AN:

176610

Hom.:

AF XY:

0.000734

AC XY:

AN XY:

64058

show subpopulations

Gnomad AFR exome

AF:

0.00409

Gnomad AMR exome

AF:

0.000295

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000615

Gnomad OTH exome

AF:

0.000923

GnomAD4 exome

AF:

0.000904

AC:

990

AN:

1095305

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

287

AN XY:

361129

show subpopulations

Gnomad4 AFR exome

AF:

0.00303

Gnomad4 AMR exome

AF:

0.000371

Gnomad4 ASJ exome

AF:

0.00224

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000946

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.00155

AC:

175

AN:

112696

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

34886

show subpopulations

Gnomad4 AFR

AF:

0.00402

Gnomad4 AMR

AF:

0.000645

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000659

Gnomad4 OTH

AF:

0.00194

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00138

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.000695

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2017

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. -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.1

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;T

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.079

Sift

Benign

0.14

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0

B;.

Vest4

0.048

MVP

0.14

MPC

0.48

ClinPred

0.0045

GERP RS

4.2

Varity_R

0.037

gMVP

0.46

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