rs1928789471

Variant names:

• chr22-37292639-G-A
• rs1928789471
• NM_013385.5:c.38G>A

Variant summary

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

The NM_013385.5(CYTH4):​c.38G>A​(p.Ser13Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.000010 (0 hom.)
• Consequence: CYTH4 NM_013385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090803295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH4	NM_013385.5	c.38G>A	p.Ser13Asn	missense_variant	Exon 2 of 13	ENST00000248901.11	NP_037517.1
CYTH4	NM_001318024.2	c.-134G>A		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.38G>A	p.Ser13Asn	missense_variant	Exon 2 of 13	1	NM_013385.5	ENSP00000248901.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461598 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727094

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38G>A (p.S13N) alteration is located in exon 2 (coding exon 2) of the CYTH4 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the serine (S) at amino acid position 13 to be replaced by an asparagine (N). 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	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.032	D;T;D;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.021	.;B;.;.
Vest4		0.20, 0.22, 0.23
MutPred		0.23		Loss of glycosylation at S13 (P = 0.0042);Loss of glycosylation at S13 (P = 0.0042);Loss of glycosylation at S13 (P = 0.0042);Loss of glycosylation at S13 (P = 0.0042);
MVP		0.47
MPC		0.39
ClinPred		0.093	T
GERP RS		3.7
Varity_R		0.068
gMVP		0.16

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: rs1928789471; hg19: chr22-37688680;