rs1010387087

Variant names:

• chr22-37300909-A-T
• rs1010387087
• NM_013385.5:c.437A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013385.5(CYTH4):​c.437A>T​(p.Gln146Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYTH4 NM_013385.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

ENSG00000298470 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

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.437A>T	p.Gln146Leu	missense splice_region	Exon 7 of 13	NP_037517.1	Q9UIA0
	CYTH4	NM_001318024.2		c.266A>T	p.Gln89Leu	missense splice_region	Exon 7 of 13	NP_001304953.1	B4E2V8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH4	ENST00000248901.11	TSL:1 MANE Select	c.437A>T	p.Gln146Leu	missense splice_region	Exon 7 of 13	ENSP00000248901.6	Q9UIA0
	CYTH4	ENST00000868416.1		c.434A>T	p.Gln145Leu	missense splice_region	Exon 7 of 13	ENSP00000538475.1
	CYTH4	ENST00000439667.1	TSL:3	n.476A>T		splice_region non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		0.91	P
Vest4		0.76
MutPred		0.37		Loss of MoRF binding (P = 0.1813)
MVP		0.81
MPC		1.2
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.58
Mutation Taster		=27/73	disease causing

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: rs1010387087; hg19: chr22-37696950;