17-78698373-T-C

Position:

• chr17-78698373-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004762.6(CYTH1):​c.707A>G​(p.Tyr236Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYTH1 NM_004762.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

Genes affected

CYTH1 (HGNC:9501): (cytohesin 1) The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of 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 activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family appear to mediate the regulation of protein sorting and membrane trafficking. This gene is highly expressed in natural killer and peripheral T cells, and regulates the adhesiveness of integrins at the plasma membrane of lymphocytes. A pseudogene of this gene has been defined on the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYTH1	NM_004762.6	c.707A>G	p.Tyr236Cys	missense_variant	9/14	ENST00000446868.8	NP_004753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYTH1	ENST00000446868.8	c.707A>G	p.Tyr236Cys	missense_variant	9/14	5	NM_004762.6	ENSP00000389095	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.707A>G (p.Y236C) alteration is located in exon 9 (coding exon 9) of the CYTH1 gene. This alteration results from a A to G substitution at nucleotide position 707, causing the tyrosine (Y) at amino acid position 236 to be replaced by a cysteine (C). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;.;.;D;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.8	.;.;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.3	.;.;.;D;D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	.;.;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.
Polyphen		1.0	.;.;D;D;D;.
Vest4		0.94
MutPred		0.71		.;.;Gain of ubiquitination at K240 (P = 0.068);Gain of ubiquitination at K240 (P = 0.068);Gain of ubiquitination at K240 (P = 0.068);.;
MVP		0.84
MPC		1.8
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.94

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

Other links and lift over

dbSNP: rs1418765318; hg19: chr17-76694455;