7-6165552-C-T

Variant names:

• chr7-6165552-C-T
• rs1376956652
• NM_004227.4:c.965G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004227.4(CYTH3):​c.965G>A​(p.Arg322Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CYTH3 NM_004227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

Genes affected

CYTH3 (HGNC:9504): (cytohesin 3) This gene encodes a member of the PSCD (pleckstrin homology, Sec7 and coiled-coil domains) family. PSCD family members 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 (GEP) 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 encoded protein is involved in the control of Golgi structure and function, and it may have a physiological role in regulating ADP-ribosylation factor protein 6 (ARF) functions, in addition to acting on ARF1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23313472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH3	NM_004227.4	c.965G>A	p.Arg322Gln	missense_variant	Exon 11 of 13	ENST00000350796.8	NP_004218.1
CYTH3	NM_001367580.1	c.710G>A	p.Arg237Gln	missense_variant	Exon 11 of 13		NP_001354509.1
CYTH3	NM_001367581.1	c.464G>A	p.Arg155Gln	missense_variant	Exon 12 of 14		NP_001354510.1
CYTH3	NM_001367582.1	c.464G>A	p.Arg155Gln	missense_variant	Exon 6 of 8		NP_001354511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH3	ENST00000350796.8	c.965G>A	p.Arg322Gln	missense_variant	Exon 11 of 13	1	NM_004227.4	ENSP00000297044.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461630 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.965G>A (p.R322Q) alteration is located in exon 11 (coding exon 11) of the CYTH3 gene. This alteration results from a G to A substitution at nucleotide position 965, causing the arginine (R) at amino acid position 322 to be replaced by a glutamine (Q). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.093
Sift	Benign	0.23	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.16	B;.
Vest4		0.47
MVP		0.34
MPC		1.6
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.65

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: rs1376956652; hg19: chr7-6205183; COSMIC: COSV60364550; COSMIC: COSV60364550;