22-37292641-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013385.5(CYTH4):​c.40G>A​(p.Gly14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CYTH4
NM_013385.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.12
Variant links:
Genes affected
CYTH4 (HGNC:9505): (cytohesin 4) This gene encodes a member of the PSCD family of proteins, which have an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family function as GEPs for ADP-ribosylation factors (ARFs), which are guanine nucleotide-binding proteins involved in vesicular trafficking pathways. This protein exhibits GEP activity in vitro with ARF1 and ARF5, but is inactive with ARF6. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.060920626).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYTH4NM_013385.5 linkc.40G>A p.Gly14Arg missense_variant Exon 2 of 13 ENST00000248901.11 NP_037517.1 Q9UIA0
CYTH4NM_001318024.2 linkc.-132G>A 5_prime_UTR_variant Exon 2 of 13 NP_001304953.1 Q9UIA0B4E2V8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYTH4ENST00000248901.11 linkc.40G>A p.Gly14Arg missense_variant Exon 2 of 13 1 NM_013385.5 ENSP00000248901.6 Q9UIA0

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
250996
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135658
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000363
AC:
53
AN:
1461560
Hom.:
0
Cov.:
30
AF XY:
0.0000385
AC XY:
28
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000990
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.40G>A (p.G14R) alteration is located in exon 2 (coding exon 2) of the CYTH4 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the glycine (G) at amino acid position 14 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

EBV-positive nodal T- and NK-cell lymphoma Benign:1
-
Department of Clinical Pathology, School of Medicine, Fujita Health University
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
18
DANN
Benign
0.93
DEOGEN2
Benign
0.0050
T;T;T;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.60
T;T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.061
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
.;L;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.21
N;N;N;N
REVEL
Benign
0.028
Sift
Benign
0.16
T;T;T;T
Sift4G
Benign
0.20
T;T;T;T
Polyphen
0.0
.;B;.;.
Vest4
0.10, 0.16, 0.16
MutPred
0.13
Gain of MoRF binding (P = 0.0776);Gain of MoRF binding (P = 0.0776);Gain of MoRF binding (P = 0.0776);Gain of MoRF binding (P = 0.0776);
MVP
0.41
MPC
0.46
ClinPred
0.024
T
GERP RS
2.5
Varity_R
0.070
gMVP
0.33

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.

Other links and lift over

dbSNP: rs201471657; hg19: chr22-37688682; API