22-37303401-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_013385.5(CYTH4):c.695G>T(p.Arg232Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CYTH4
NM_013385.5 missense, splice_region

Scores

Splicing: ADA: 0.01176

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

4 publications found

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]

CYTH4 links:

ENSG00000298470 (HGNC:):

ENSG00000298470 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26484996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013385.5. 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
	CYTH4	NM_013385.5	MANE Select	c.695G>T	p.Arg232Leu	missense splice_region	Exon 8 of 13	NP_037517.1	Q9UIA0
	CYTH4	NM_001318024.2		c.524G>T	p.Arg175Leu	missense splice_region	Exon 8 of 13	NP_001304953.1	B4E2V8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYTH4	ENST00000248901.11	TSL:1 MANE Select	c.695G>T	p.Arg232Leu	missense splice_region	Exon 8 of 13	ENSP00000248901.6	Q9UIA0
CYTH4	ENST00000868416.1		c.692G>T	p.Arg231Leu	missense splice_region	Exon 8 of 13	ENSP00000538475.1
CYTH4	ENST00000462927.5	TSL:2	n.740G>T		splice_region non_coding_transcript_exon	Exon 8 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249068

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460296

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111442

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.019

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.7

REVEL

Benign

0.11

Sift

Benign

0.078

Sift4G

Benign

0.24

Polyphen

0.22

Vest4

0.48

MutPred

0.36

Loss of loop (P = 0.1258)

MVP

0.71

MPC

0.59

ClinPred

0.17

GERP RS

3.4

Varity_R

0.14

gMVP

0.55

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.046

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over