Genetic Variant VCF2:p.Cys4Phe (chrX-55161146-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001166701.4(VCF2):c.11G>T(p.Cys4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,206,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.00016 ( 0 hom. 56 hem. )

Consequence

VCF2
NM_001166701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.00

Variant links:

Genes affected

VCF2 (HGNC:25085): (VCP nuclear cofactor family member 2)

VCF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07605621).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCF2	NM_001166701.4 link	c.11G>T	p.Cys4Phe	missense_variant	Exon 1 of 3	ENST00000685693.1	NP_001160173.1	A0A8I5KUH0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM104B	ENST00000685693.1 link	c.11G>T	p.Cys4Phe	missense_variant	Exon 1 of 3		NM_001166701.4	ENSP00000509111.1		A0A8I5KUH0

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112580

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34738

show subpopulations

Gnomad AFR

AF:

0.000129

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000760

AC:

AN:

171155

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

58063

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000150

Gnomad SAS exome

AF:

0.0000570

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

170

AN:

1094265

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

360183

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000750

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000392

GnomAD4 genome

AF:

0.000107

AC:

AN:

112630

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34798

show subpopulations

Gnomad4 AFR

AF:

0.000129

Gnomad4 AMR

AF:

0.0000925

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000587

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000743

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11G>T (p.C4F) alteration is located in exon 1 (coding exon 1) of the FAM104B gene. This alteration results from a G to T substitution at nucleotide position 11, causing the cysteine (C) at amino acid position 4 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.84

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.019

.;T;.;.

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.43

T;T;T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.076

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

N;N;N;D

REVEL

Benign

0.018

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.014

B;B;B;.

Vest4

0.26

MVP

0.088

MPC

0.54

ClinPred

0.055

GERP RS

-0.92

Varity_R

0.56

gMVP

0.050

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