22-37292623-C-G

Variant names:

• chr22-37292623-C-G
• rs751140524
• NM_013385.5:c.22C>G

Variant summary

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

The NM_013385.5(CYTH4):​c.22C>G​(p.Pro8Ala) 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 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYTH4 NM_013385.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0410

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH4	NM_013385.5	c.22C>G	p.Pro8Ala	missense_variant, splice_region_variant	Exon 2 of 13	ENST00000248901.11	NP_037517.1
CYTH4	NM_001318024.2	c.-150C>G		5_prime_UTR_variant	Exon 2 of 13		NP_001304953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH4	ENST00000248901.11	c.22C>G	p.Pro8Ala	missense_variant, splice_region_variant	Exon 2 of 13	1	NM_013385.5	ENSP00000248901.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461354 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726976

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22C>G (p.P8A) alteration is located in exon 2 (coding exon 2) of the CYTH4 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the proline (P) at amino acid position 8 to be replaced by an alanine (A). 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	Benign	0.052
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.3
DANN	Benign	0.96
DEOGEN2	Benign	0.066	T;T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;N;D;D
REVEL	Benign	0.071
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		0.020	.;B;.;.
Vest4		0.20, 0.22, 0.19
MutPred		0.28		Loss of glycosylation at P8 (P = 0.0707);Loss of glycosylation at P8 (P = 0.0707);Loss of glycosylation at P8 (P = 0.0707);Loss of glycosylation at P8 (P = 0.0707);
MVP		0.40
MPC		0.37
ClinPred		0.16	T
GERP RS		2.7
Varity_R		0.036
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs751140524; hg19: chr22-37688664;