22-37297648-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013385.5(CYTH4):​c.319A>C​(p.Asn107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,890 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00074 ( 11 hom. )

Consequence

CYTH4
NM_013385.5 missense

Scores

4
7
7

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.31
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01158908).
BP6
Variant 22-37297648-A-C is Benign according to our data. Variant chr22-37297648-A-C is described in ClinVar as [Benign]. Clinvar id is 734145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00704 (1072/152320) while in subpopulation AFR AF= 0.0249 (1034/41564). AF 95% confidence interval is 0.0236. There are 11 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYTH4NM_013385.5 linkc.319A>C p.Asn107His missense_variant Exon 5 of 13 ENST00000248901.11 NP_037517.1 Q9UIA0
CYTH4NM_001318024.2 linkc.148A>C p.Asn50His 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.319A>C p.Asn107His missense_variant Exon 5 of 13 1 NM_013385.5 ENSP00000248901.6 Q9UIA0

Frequencies

GnomAD3 genomes
AF:
0.00703
AC:
1070
AN:
152202
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0249
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00575
GnomAD3 exomes
AF:
0.00178
AC:
448
AN:
251480
Hom.:
5
AF XY:
0.00111
AC XY:
151
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0253
Gnomad AMR exome
AF:
0.000781
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000744
AC:
1088
AN:
1461570
Hom.:
11
Cov.:
30
AF XY:
0.000646
AC XY:
470
AN XY:
727094
show subpopulations
Gnomad4 AFR exome
AF:
0.0278
Gnomad4 AMR exome
AF:
0.000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00156
GnomAD4 genome
AF:
0.00704
AC:
1072
AN:
152320
Hom.:
11
Cov.:
32
AF XY:
0.00655
AC XY:
488
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0249
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00569
Alfa
AF:
0.00163
Hom.:
4
Bravo
AF:
0.00843
ESP6500AA
AF:
0.0229
AC:
101
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00215
AC:
261
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Jun 05, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;T;T;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;D
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Pathogenic
3.6
.;H;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-4.8
D;D;D;D
REVEL
Uncertain
0.35
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0
.;D;.;.
Vest4
0.71, 0.68, 0.68
MVP
0.81
MPC
1.2
ClinPred
0.075
T
GERP RS
4.0
Varity_R
0.74
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs73887107; hg19: chr22-37693689; API