rs781788935

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_005334.3(HCFC1):c.4619C>T(p.Thr1540Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,192,624 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 26)

Exomes 𝑓: 0.000032 ( 0 hom. 10 hem. )

Consequence

HCFC1
NM_005334.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0410

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 -8 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=0.03781441).

BP6

Variant X-153952837-G-A is Benign according to our data. Variant chrX-153952837-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424226.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCFC1	NM_005334.3 linkuse as main transcript	c.4619C>T	p.Thr1540Ile	missense_variant	19/26	ENST00000310441.12	NP_005325.2	P51610-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCFC1	ENST00000310441.12 linkuse as main transcript	c.4619C>T	p.Thr1540Ile	missense_variant	19/26	1	NM_005334.3	ENSP00000309555.7	P51610-1
HCFC1	ENST00000369984.4 linkuse as main transcript	c.4751C>T	p.Thr1584Ile	missense_variant	19/26	5		ENSP00000359001.4	A6NEM2
HCFC1	ENST00000444191.5 linkuse as main transcript	c.341C>T	p.Thr114Ile	missense_variant	3/10	5		ENSP00000399589.1	H7C1C4

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112991

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

35119

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

144008

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

42976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000658

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000324

AC:

AN:

1079633

Hom.:

Cov.:

AF XY:

0.0000285

AC XY:

AN XY:

350339

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000302

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000408

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112991

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

35119

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000926

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 28, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2017

The T1540I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T1540I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1540I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Methylmalonic acidemia with homocystinuria, type cblX

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.90

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.032

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.072

T;T

Polyphen

0.0020

B;.

Vest4

0.026

MutPred

0.21

Loss of phosphorylation at T1540 (P = 0.0172);.;

MVP

0.11

MPC

0.59

ClinPred

0.021

GERP RS

-2.4

Varity_R

0.097

gMVP

0.47

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