22-37297639-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013385.5(CYTH4):​c.310G>A​(p.Glu104Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

CYTH4
NM_013385.5 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.99
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYTH4NM_013385.5 linkc.310G>A p.Glu104Lys missense_variant Exon 5 of 13 ENST00000248901.11 NP_037517.1 Q9UIA0
CYTH4NM_001318024.2 linkc.139G>A p.Glu47Lys missense_variant Exon 5 of 13 NP_001304953.1 Q9UIA0B4E2V8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYTH4ENST00000248901.11 linkc.310G>A p.Glu104Lys missense_variant Exon 5 of 13 1 NM_013385.5 ENSP00000248901.6 Q9UIA0

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251484
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000664
AC:
97
AN:
1461666
Hom.:
0
Cov.:
30
AF XY:
0.0000646
AC XY:
47
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000827
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.310G>A (p.E104K) alteration is located in exon 5 (coding exon 5) of the CYTH4 gene. This alteration results from a G to A substitution at nucleotide position 310, causing the glutamic acid (E) at amino acid position 104 to be replaced by a lysine (K). 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
0.26
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.056
T;T;T;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.44
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
.;M;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Uncertain
0.31
Sift
Uncertain
0.0010
D;T;D;D
Sift4G
Uncertain
0.0020
D;T;D;D
Polyphen
0.17
.;B;.;.
Vest4
0.70, 0.70
MVP
0.50
MPC
0.81
ClinPred
0.81
D
GERP RS
4.0
Varity_R
0.57
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs372562479; hg19: chr22-37693680; COSMIC: COSV50634012; COSMIC: COSV50634012; API