X-55161146-C-A

Variant names:

• chrX-55161146-C-A
• rs146914917
• NM_001166701.4:c.11G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C4Y) has been classified 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.00
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07605621).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166701.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCF2	NM_001166701.4	MANE Select	c.11G>T	p.Cys4Phe	missense	Exon 1 of 3	NP_001160173.1	A0A8I5KUH0
	VCF2	NM_001166699.2		c.11G>T	p.Cys4Phe	missense	Exon 1 of 4	NP_001160171.1	Q5XKR9-2
	VCF2	NM_001166700.2		c.11G>T	p.Cys4Phe	missense	Exon 1 of 3	NP_001160172.1	Q5XKR9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCF2	ENST00000685693.1	MANE Select	c.11G>T	p.Cys4Phe	missense	Exon 1 of 3	ENSP00000509111.1	A0A8I5KUH0
	VCF2	ENST00000332132.8	TSL:1	c.11G>T	p.Cys4Phe	missense	Exon 1 of 4	ENSP00000333394.4	Q5XKR9-2
	VCF2	ENST00000358460.8	TSL:1	c.11G>T	p.Cys4Phe	missense	Exon 1 of 4	ENSP00000364101.3	Q5XKR9-1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 112580 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.0000760 AC: 13 AN: 171155 AF XY: 0.0000517

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 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.: 0 Cov.: 31 AF XY: 0.000155 AC XY: 56 AN XY: 360183

African (AFR) AF: 0.0000379 AC: 1 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 34874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19282

East Asian (EAS) AF: 0.00 AC: 0 AN: 30068

South Asian (SAS) AF: 0.0000750 AC: 4 AN: 53312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.000175 AC: 147 AN: 840184

Other (OTH) AF: 0.000392 AC: 18 AN: 45936

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112630 Hom.: 0 Cov.: 24 AF XY: 0.000115 AC XY: 4 AN XY: 34798

African (AFR) AF: 0.000129 AC: 4 AN: 31052

American (AMR) AF: 0.0000925 AC: 1 AN: 10814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53208

Other (OTH) AF: 0.00 AC: 0 AN: 1554

Alfa AF: 0.0000594 Hom.: 3

Bravo AF: 0.000162

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000743 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.018
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.014	B
Vest4		0.26
MVP		0.088
MPC		0.54
ClinPred		0.055	T
GERP RS		-0.92
PromoterAI		-0.019	Neutral
Varity_R		0.56
gMVP		0.050
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146914917; hg19: chrX-55187579;